S. Andrew Josephson, MD

The approach to clinical conundrums by an expert clinician is revealed through the presentation of an actual patient’s case in an approach typical of a morning report. Similarly to patient care, sequential pieces of information are provided to the clinician, who is unfamiliar with the case. The focus is on the thought processes of both the clinical team caring for the patient and the discussant.

A 78-year-old woman presented to her primary care physician with a 2-month history of progressive leg weakness. She reported walking difficulty caused by occasional “buckling” of the knees.

The knee buckling may be a clue to the quadriceps muscle weakness. The quadriceps straightens and locks the knee when the foot is being planted. Weakness of this muscle can result in the knee giving way. Isolated quadriceps weakness, which is uncommon, typically is caused by lower motor neuron issues, such as femoral neuropathy, L4–L5 radiculopathy, lumbosacral plexopathy, and primary muscle diseases, including inclusion body myositis.

The patient had diabetes mellitus and hypertension. Her medications were insulin glargine, metformin, glipizide, lisinopril, atorvastatin, and aspirin, and she was taking vitamin D and calcium. None of these was recently changed or added. Aside from having the weakness, the patient was in her usual state of health and had no other complaints. She denied weight changes, fevers, night sweats, and fatigue. She was widowed, lived with her daughter, had no pets, never used tobacco, and did not drink alcohol or use illicit drugs. There was no family history of neuromuscular disorders, and both of her parents died of natural causes at advanced ages.

The physical examination revealed no knee deformities, and the patient had good active range of motion of both knees and normal strength throughout her limbs. Plain radiographs of the knees showed mild medial compartment osteoarthritis. The patient was advised to stop atorvastatin.

Patients who take atorvastatin and other statins (3-hydroxy-3-methyl-glutaryl-co-enzyme A reductase inhibitors) can experience a spectrum of muscle disease, from myalgias and weakness to (rare) overt myositis with rhabdomyolysis. Statin-induced myopathy tends to affect larger proximal muscles, can occur at any time during the period the medication is being used, and usually resolves within weeks after discontinuation. Given this patient’s preserved strength, it was reasonable to manage her conservatively.

One month later, she presented to another hospital’s emergency department with increasing weakness in the lower extremities and new loss of balance requiring use of a walker for ambulation. She thought the weakness was confined to her legs and was affecting her thigh muscles more than her calves or feet. She reported fatigue, decreased appetite, and an unintentional 15-pound weight loss. She denied diarrhea, back pain, bowel and bladder function problems, sensation changes, myalgias, and arthralgias. She reported no swallowing or vision problems, rashes, Raynaud disease symptoms, photosensitivity, dry eyes or mouth, recent falls or trauma, fevers, night sweats, recent illness, or travel.

On physical examination, the patient’s temperature was 98.2°F, blood pressure 120/84 mm Hg, pulse 73 beats per minute, respiratory rate 16 breaths per minute, and oxygen saturation 99% with ambient air. The patient was obese and not in distress. She was alert, oriented, and able to follow multistep instructions. Cranial nerve examination was normal. The patient had mild weakness in her bilateral deltoids and bilateral hip flexors but full strength in all other muscle groups. Deep tendon reflexes were normal in the biceps and patella and reduced in the ankles. The Babinski sign was absent. Throughout the lower extremities, sensation was intact to light touch; there was no saddle anesthesia. Finger–nose–finger testing showed slight dysmetria in the left upper extremity. Because of her imbalance, the patient needed help to stand up; once upright, though, she was able to take 3 steps forward and backward with use of a walker. Her stride length was diminished, and her gait unsteady and wide based.

These exam findings suggest 2 separate localizations. Symmetric proximal weakness with preserved distal strength in the extremities indicate a lower motor neuron problem, further suggested by the absence of upper motor neuron findings of spasticity, and hyperreflexia. Intact patellar and biceps reflexes suggest either muscle or neuromuscular junction localization. Separately, the findings of wide-based gait and dysmetria raise the possibility of a problem in the ipsilateral cerebellum, in this case on the left. A cerebellar lesion would not explain the bilateral symmetric weakness. The combination of lower motor neuron leg weakness and cerebellar deficits suggests a systemic disorder, such as an infectious, inflammatory, or paraneoplastic process. A space-occupying lesion would not produce this constellation of deficits.

Serum chemistry panel was normal, creatinine level 0.47 mg/dL, and albumin level 4.0 g/dL. White blood cell (WBC) count was 8100/mm³, hemoglobin level 12 g/dL, and platelet count 287,000/mm³. Alanine aminotransferase (ALT) level was 74 U/L (reference range, 0-36 U/L), alkaline phosphatase level 41 U/L (reference range, 37-117 U/L), and total bilirubin level 0.4 mg/dL (reference range, 0.2-1.2 mg/dL). Prothrombin time and thyrotropin were normal. Creatine kinase (CK) level was 2328 U/L (reference range, <200 U/L). Erythrocyte sedimentation rate was 17 mm/h, and C-reactive protein level 0.1 mg/L. Urinalysis (dipstick testing) detected no myoglobin, and there were no casts. Plain radiograph of the chest was normal.

The elevated CK indicates muscle disease, and, in the absence of other findings of liver disease, the ALT elevation likely has a muscle origin as well. The differential diagnosis for elevated CK includes myopathy caused either by infection, trauma, ischemia, or a toxin (medication included) or by a hereditary, metabolic, endocrinologic, or inflammatory disorder. There is no history of trauma, strenuous exertion, or muscle toxin other than the statin, and the progression of symptoms after medication discontinuation argues against statin myopathy. The laboratory test results rule out derangement of potassium, calcium, phosphorus, magnesium, vitamin D, or thyroid function as the cause of the myopathy. The absence of fever, absence of diffuse organ involvement, and normal inflammatory markers point away from a systemic infection or vasculitis. The inflammatory myopathies dermatomyositis and polymyositis classically produce proximal muscle weakness and are possibilities in this case, but one would expect the inflammatory markers to be elevated in these conditions. Malignancy related to dermatomyositis or to paraneoplastic syndrome may account for the myopathy.

The data provided do not identify a unifying diagnosis. To look for an inflammatory myopathy, such as dermatomyositis or polymyositis, it is reasonable to perform electromyography (EMG) to delineate the location of muscle involvement and identify a site for tissue biopsy. As no obvious toxins or metabolic conditions explain the dysmetria, magnetic resonance imaging (MRI) of the brain should be performed to evaluate for lesions in the cerebellum.

The patient was admitted to the hospital. On T2-weighted and FLAIR (fluid attenuation inversion recovery) sequences, MRI of the brain showed a few scattered subcortical and periventricular white matter hyperintense foci bilaterally. Antibodies to human immunodeficiency virus 1 and 2, and Treponema pallidum immunoglobulins G and M, were not detected. Serum levels of lactate dehydrogenase, vitamin B ₁₂ , angiotensin-converting enzyme, antinuclear antibody, rheumatoid factor, and anti–cyclic citrullinated peptide IgG were normal.

The brain imaging excludes a space-occupying lesion in the cerebellum but does not identify the cause of dysmetria. Toxic-metabolic conditions, such as alcohol toxicity, vitamin B₁₂ deficiency, anoxia, and toxicity of certain medications, may impair cerebellar function (MRI findings may be normal), but none of these is present. Other disorders that attack the central nervous system (CNS) (again, brain imaging may show minimal abnormalities) include infections, early-stage neurodegenerative illnesses, and antibody-associated disorders (eg, autoimmune diseases, postinfectious and paraneoplastic conditions).

Four days after intravenous fluids were started, the patient’s CK level improved, but her weakness persisted. There was no evidence of peripheral neuropathy on lower extremity nerve conduction studies. EMG revealed few fibrillations and positive sharp waves in proximal limb muscles and thoracic paraspinal muscles. Deltoid, biceps, and tensor fasciae latae showed shorter duration complex motor units with early recruitment. The patient declined muscle biopsy. A rheumatologist was consulted, and prednisone 60 mg/d was started for possible inflammatory myopathy. The patient was discharged to a skilled nursing facility for physical therapy.

The fibrillations and positive sharp waves on EMG can be seen in both neuropathy (from denervation) and myopathy. The normal nerve conduction studies make localization to the nerve unlikely. In addition, the shorter duration motor units with early recruitment on EMG are characteristic of a myopathy. Despite the ongoing myopathy, the improved CK level suggests the muscle disease is playing a minimal role in the patient’s current illness. Prescribing corticosteroids for a presumed inflammatory myopathy without a clear diagnosis is risky, as steroids may render subsequent biopsy results unreliable, may themselves cause myopathy, and expose the patient to the side effects of immunosuppression.

One month later, the patient saw her rheumatologist. Although she had tapered the prednisone down to 10 mg/d, she had not returned to baseline strength, was still using a walker, and reported increased difficulty keeping her head raised. She also noted 2 new symptoms: speech slurring and, in both hands, a tremor that made it difficult to hold objects.

Examination revealed a fine tremor in both arms. There were no skin lesions, and the joints were normal. The patient was oriented to name, place, and date. Memory testing was 3 for 3 on register but 0 for 3 on recall. She was unable to perform serial 7s and able to spell backward only 3 of the 5 letters in the word world . Speech was dysarthric and scanning in quality. On extraocular movements, she demonstrated poor smooth pursuit. Examination of the head and neck was significant for nearly constant head titubation and weak neck flexors. Upper extremity strength was normal. Mild weakness was noted in both hip flexors. Deep tendon reflexes were preserved except at the ankle, where they were reduced. Finger–nose–finger testing revealed marked dysmetria, more pronounced on the left, and there was mild bilateral heel-to-shin dysmetria.

Diffuse myopathy cannot account for the patient’s impaired cognition or progressive cerebellar findings, which now include head titubation and scanning speech. As more than a month has elapsed since the brain imaging was performed, MRI could be repeated for evidence of infection, malignancy, inflammation, or demyelination. More important, lumbar puncture is indicated to exclude infection and, with flow cytometry, cytology, and measurement of oligoclonal bands and IgG index, to assess for autoimmune or paraneoplastic antibody-mediated disorders.

The patient was readmitted. On repeat brain MRI, there were no new significant findings. Complete blood cell count and chemistry panel results were unremarkable. Erythrocyte sedimentation rate and C-reactive protein level remained normal. CK level was 451 U/L, and ALT level 29 U/L.

Lumbar puncture was performed. Opening pressure was 14.5 cm of water, and cerebrospinal fluid (CSF) was clear and colorless. There were 3 red blood cells/mm ³ and no WBCs. Glucose level was 94 mg/dL, and protein level 74 mg/dL. CSF IgG synthesis rate was normal, flow cytometry revealed no abnormal clonal populations, and cytology was negative for malignancy. Two unique oligoclonal bands were found in the CSF.

The absence of WBCs in the CSF excludes CNS infection. The patient’s main problem is an inflammatory CNS process as defined by presence of oligoclonal bands in the CSF, compared with their absence in the serum. Autoimmune, neoplastic, and paraneoplastic disorders could explain these bands. There was no evidence of systemic autoimmune illness. The patient has not had a recent infection that could result in postinfectious demyelination, and her clinical and imaging features are not suggestive of a demyelinating disorder, such as multiple sclerosis. Of the neoplastic possibilities, lymphoma with CNS involvement may be difficult to detect initially; this diagnosis, however, is not supported by the unremarkable MRI, flow cytometry, and cytology findings. In paraneoplastic syndromes, the CSF may include antibodies that react to antigens in the brain or cerebellum.

At this point, evaluation for malignancy should involve mammography, imaging of the chest, abdomen, and pelvis, and colorectal screening. Testing should also include measurement of serum and CSF autoantibodies associated with paraneoplastic cerebellar degeneration. The expanding list of paraneoplastic antibodies that may attack the cerebellum includes anti-Hu (often associated with small cell lung cancer), anti-Yo (associated with ovarian or breast cancer), anti-aquaporin 4, antibodies to the voltage-gated potassium channel, and anti–glutamic acid decarboxylase (anti-GAD).

Mammography and breast examination findings were normal. Computed tomography (CT) of the chest showed no adenopathy, nodules, or masses. Abdomen CT showed nonspecific prominence of the gallbladder wall. Flexible sigmoidoscopy revealed no masses, only thickened folds in the sigmoid colon; results of multiple colon biopsy tests were normal. Carcinoembryonic antigen level was 2.0 μg/L, and CA-125 level 5 U/mL. Serum GAD-65 antibodies were elevated (>30 nmol/L).

Anti-GAD is mostly known as the antibody associated with type 1 diabetes mellitus (T1DM). In rare instances, even in patients without a history of diabetes, anti-GAD antibodies may lead to an autoimmune attack on the brain, particularly the cerebellum, as part of an idiopathic autoimmune disorder or as a paraneoplastic syndrome. In either case, treatment involves corticosteroids, intravenous Ig, or plasma exchange. When the autoimmune attack is associated with malignancy, treatment response is poorer, unless the malignancy is successfully managed. The next steps are intravenous Ig or plasma exchange and positron emission tomography–CT (PET-CT) assessing for an underlying neoplasm that may have been too small to be detected with routine CT.

Numerous antibodies to antigens of the nervous system have been identified in association with malignancy, resulting in a variety of paraneoplastic neurologic syndromes (PNSs). Collectively, these syndromes are seen in fewer than 1 in 10,000 patients with cancer. The malignancy may be diagnosed months to years before the paraneoplastic syndrome, or the syndrome may be the first clue to underlying malignancy.¹ Hospitalists should suspect a PNS if the patient has known cancer and has unexplained neurologic deficits, if the presentation fits a classic PNS pattern, or if evaluation for neurologic symptoms identifies an inflammatory CSF profile that cannot be explained by demyelinating disorder or infection.

• The differential diagnosis for cerebellar deficits associated with normal brain MRI includes infection, toxic-metabolic insults (alcohol toxicity, vitamin B₁₂ deficiency, medication toxicity), anoxia, early neurodegenerative illness, and antibody-mediated disorders, such as autoimmune, postinfectious, and paraneoplastic syndromes.
• Hospitalists should suspect a PNS when a patient with known cancer develops unexplained neurologic deficits or when evaluation for neurologic symptoms identifies an inflammatory CSF profile that cannot be explained by a demyelinating disorder or an infection.
• Hospitalists should familiarize themselves with the classic PNS presentations, including limbic encephalitis, cerebellar degeneration, stiff person syndrome, opsoclonus-myoclonus, NMDA receptor encephalitis, and encephalomyelitis.
• Suspicion for PNS may be confirmed by the presence of paraneoplastic antibodies in CSF or serum. When routine evaluation fails to identify cancer, PET-CT should be performed.

Disclosure

Nothing to report.

The approach to clinical conundrums by an expert clinician is revealed through the presentation of an actual patient’s case in an approach typical of a morning report. Similarly to patient care, sequential pieces of information are provided to the clinician, who is unfamiliar with the case. The focus is on the thought processes of both the clinical team caring for the patient and the discussant.

A 78-year-old woman presented to her primary care physician with a 2-month history of progressive leg weakness. She reported walking difficulty caused by occasional “buckling” of the knees.

The knee buckling may be a clue to the quadriceps muscle weakness. The quadriceps straightens and locks the knee when the foot is being planted. Weakness of this muscle can result in the knee giving way. Isolated quadriceps weakness, which is uncommon, typically is caused by lower motor neuron issues, such as femoral neuropathy, L4–L5 radiculopathy, lumbosacral plexopathy, and primary muscle diseases, including inclusion body myositis.

The patient had diabetes mellitus and hypertension. Her medications were insulin glargine, metformin, glipizide, lisinopril, atorvastatin, and aspirin, and she was taking vitamin D and calcium. None of these was recently changed or added. Aside from having the weakness, the patient was in her usual state of health and had no other complaints. She denied weight changes, fevers, night sweats, and fatigue. She was widowed, lived with her daughter, had no pets, never used tobacco, and did not drink alcohol or use illicit drugs. There was no family history of neuromuscular disorders, and both of her parents died of natural causes at advanced ages.

The physical examination revealed no knee deformities, and the patient had good active range of motion of both knees and normal strength throughout her limbs. Plain radiographs of the knees showed mild medial compartment osteoarthritis. The patient was advised to stop atorvastatin.

Patients who take atorvastatin and other statins (3-hydroxy-3-methyl-glutaryl-co-enzyme A reductase inhibitors) can experience a spectrum of muscle disease, from myalgias and weakness to (rare) overt myositis with rhabdomyolysis. Statin-induced myopathy tends to affect larger proximal muscles, can occur at any time during the period the medication is being used, and usually resolves within weeks after discontinuation. Given this patient’s preserved strength, it was reasonable to manage her conservatively.

One month later, she presented to another hospital’s emergency department with increasing weakness in the lower extremities and new loss of balance requiring use of a walker for ambulation. She thought the weakness was confined to her legs and was affecting her thigh muscles more than her calves or feet. She reported fatigue, decreased appetite, and an unintentional 15-pound weight loss. She denied diarrhea, back pain, bowel and bladder function problems, sensation changes, myalgias, and arthralgias. She reported no swallowing or vision problems, rashes, Raynaud disease symptoms, photosensitivity, dry eyes or mouth, recent falls or trauma, fevers, night sweats, recent illness, or travel.

On physical examination, the patient’s temperature was 98.2°F, blood pressure 120/84 mm Hg, pulse 73 beats per minute, respiratory rate 16 breaths per minute, and oxygen saturation 99% with ambient air. The patient was obese and not in distress. She was alert, oriented, and able to follow multistep instructions. Cranial nerve examination was normal. The patient had mild weakness in her bilateral deltoids and bilateral hip flexors but full strength in all other muscle groups. Deep tendon reflexes were normal in the biceps and patella and reduced in the ankles. The Babinski sign was absent. Throughout the lower extremities, sensation was intact to light touch; there was no saddle anesthesia. Finger–nose–finger testing showed slight dysmetria in the left upper extremity. Because of her imbalance, the patient needed help to stand up; once upright, though, she was able to take 3 steps forward and backward with use of a walker. Her stride length was diminished, and her gait unsteady and wide based.

These exam findings suggest 2 separate localizations. Symmetric proximal weakness with preserved distal strength in the extremities indicate a lower motor neuron problem, further suggested by the absence of upper motor neuron findings of spasticity, and hyperreflexia. Intact patellar and biceps reflexes suggest either muscle or neuromuscular junction localization. Separately, the findings of wide-based gait and dysmetria raise the possibility of a problem in the ipsilateral cerebellum, in this case on the left. A cerebellar lesion would not explain the bilateral symmetric weakness. The combination of lower motor neuron leg weakness and cerebellar deficits suggests a systemic disorder, such as an infectious, inflammatory, or paraneoplastic process. A space-occupying lesion would not produce this constellation of deficits.

Serum chemistry panel was normal, creatinine level 0.47 mg/dL, and albumin level 4.0 g/dL. White blood cell (WBC) count was 8100/mm³, hemoglobin level 12 g/dL, and platelet count 287,000/mm³. Alanine aminotransferase (ALT) level was 74 U/L (reference range, 0-36 U/L), alkaline phosphatase level 41 U/L (reference range, 37-117 U/L), and total bilirubin level 0.4 mg/dL (reference range, 0.2-1.2 mg/dL). Prothrombin time and thyrotropin were normal. Creatine kinase (CK) level was 2328 U/L (reference range, <200 U/L). Erythrocyte sedimentation rate was 17 mm/h, and C-reactive protein level 0.1 mg/L. Urinalysis (dipstick testing) detected no myoglobin, and there were no casts. Plain radiograph of the chest was normal.

The elevated CK indicates muscle disease, and, in the absence of other findings of liver disease, the ALT elevation likely has a muscle origin as well. The differential diagnosis for elevated CK includes myopathy caused either by infection, trauma, ischemia, or a toxin (medication included) or by a hereditary, metabolic, endocrinologic, or inflammatory disorder. There is no history of trauma, strenuous exertion, or muscle toxin other than the statin, and the progression of symptoms after medication discontinuation argues against statin myopathy. The laboratory test results rule out derangement of potassium, calcium, phosphorus, magnesium, vitamin D, or thyroid function as the cause of the myopathy. The absence of fever, absence of diffuse organ involvement, and normal inflammatory markers point away from a systemic infection or vasculitis. The inflammatory myopathies dermatomyositis and polymyositis classically produce proximal muscle weakness and are possibilities in this case, but one would expect the inflammatory markers to be elevated in these conditions. Malignancy related to dermatomyositis or to paraneoplastic syndrome may account for the myopathy.

The data provided do not identify a unifying diagnosis. To look for an inflammatory myopathy, such as dermatomyositis or polymyositis, it is reasonable to perform electromyography (EMG) to delineate the location of muscle involvement and identify a site for tissue biopsy. As no obvious toxins or metabolic conditions explain the dysmetria, magnetic resonance imaging (MRI) of the brain should be performed to evaluate for lesions in the cerebellum.

The patient was admitted to the hospital. On T2-weighted and FLAIR (fluid attenuation inversion recovery) sequences, MRI of the brain showed a few scattered subcortical and periventricular white matter hyperintense foci bilaterally. Antibodies to human immunodeficiency virus 1 and 2, and Treponema pallidum immunoglobulins G and M, were not detected. Serum levels of lactate dehydrogenase, vitamin B ₁₂ , angiotensin-converting enzyme, antinuclear antibody, rheumatoid factor, and anti–cyclic citrullinated peptide IgG were normal.

The brain imaging excludes a space-occupying lesion in the cerebellum but does not identify the cause of dysmetria. Toxic-metabolic conditions, such as alcohol toxicity, vitamin B₁₂ deficiency, anoxia, and toxicity of certain medications, may impair cerebellar function (MRI findings may be normal), but none of these is present. Other disorders that attack the central nervous system (CNS) (again, brain imaging may show minimal abnormalities) include infections, early-stage neurodegenerative illnesses, and antibody-associated disorders (eg, autoimmune diseases, postinfectious and paraneoplastic conditions).

Four days after intravenous fluids were started, the patient’s CK level improved, but her weakness persisted. There was no evidence of peripheral neuropathy on lower extremity nerve conduction studies. EMG revealed few fibrillations and positive sharp waves in proximal limb muscles and thoracic paraspinal muscles. Deltoid, biceps, and tensor fasciae latae showed shorter duration complex motor units with early recruitment. The patient declined muscle biopsy. A rheumatologist was consulted, and prednisone 60 mg/d was started for possible inflammatory myopathy. The patient was discharged to a skilled nursing facility for physical therapy.

The fibrillations and positive sharp waves on EMG can be seen in both neuropathy (from denervation) and myopathy. The normal nerve conduction studies make localization to the nerve unlikely. In addition, the shorter duration motor units with early recruitment on EMG are characteristic of a myopathy. Despite the ongoing myopathy, the improved CK level suggests the muscle disease is playing a minimal role in the patient’s current illness. Prescribing corticosteroids for a presumed inflammatory myopathy without a clear diagnosis is risky, as steroids may render subsequent biopsy results unreliable, may themselves cause myopathy, and expose the patient to the side effects of immunosuppression.

One month later, the patient saw her rheumatologist. Although she had tapered the prednisone down to 10 mg/d, she had not returned to baseline strength, was still using a walker, and reported increased difficulty keeping her head raised. She also noted 2 new symptoms: speech slurring and, in both hands, a tremor that made it difficult to hold objects.

Examination revealed a fine tremor in both arms. There were no skin lesions, and the joints were normal. The patient was oriented to name, place, and date. Memory testing was 3 for 3 on register but 0 for 3 on recall. She was unable to perform serial 7s and able to spell backward only 3 of the 5 letters in the word world . Speech was dysarthric and scanning in quality. On extraocular movements, she demonstrated poor smooth pursuit. Examination of the head and neck was significant for nearly constant head titubation and weak neck flexors. Upper extremity strength was normal. Mild weakness was noted in both hip flexors. Deep tendon reflexes were preserved except at the ankle, where they were reduced. Finger–nose–finger testing revealed marked dysmetria, more pronounced on the left, and there was mild bilateral heel-to-shin dysmetria.

Diffuse myopathy cannot account for the patient’s impaired cognition or progressive cerebellar findings, which now include head titubation and scanning speech. As more than a month has elapsed since the brain imaging was performed, MRI could be repeated for evidence of infection, malignancy, inflammation, or demyelination. More important, lumbar puncture is indicated to exclude infection and, with flow cytometry, cytology, and measurement of oligoclonal bands and IgG index, to assess for autoimmune or paraneoplastic antibody-mediated disorders.

The patient was readmitted. On repeat brain MRI, there were no new significant findings. Complete blood cell count and chemistry panel results were unremarkable. Erythrocyte sedimentation rate and C-reactive protein level remained normal. CK level was 451 U/L, and ALT level 29 U/L.

Lumbar puncture was performed. Opening pressure was 14.5 cm of water, and cerebrospinal fluid (CSF) was clear and colorless. There were 3 red blood cells/mm ³ and no WBCs. Glucose level was 94 mg/dL, and protein level 74 mg/dL. CSF IgG synthesis rate was normal, flow cytometry revealed no abnormal clonal populations, and cytology was negative for malignancy. Two unique oligoclonal bands were found in the CSF.

The absence of WBCs in the CSF excludes CNS infection. The patient’s main problem is an inflammatory CNS process as defined by presence of oligoclonal bands in the CSF, compared with their absence in the serum. Autoimmune, neoplastic, and paraneoplastic disorders could explain these bands. There was no evidence of systemic autoimmune illness. The patient has not had a recent infection that could result in postinfectious demyelination, and her clinical and imaging features are not suggestive of a demyelinating disorder, such as multiple sclerosis. Of the neoplastic possibilities, lymphoma with CNS involvement may be difficult to detect initially; this diagnosis, however, is not supported by the unremarkable MRI, flow cytometry, and cytology findings. In paraneoplastic syndromes, the CSF may include antibodies that react to antigens in the brain or cerebellum.

At this point, evaluation for malignancy should involve mammography, imaging of the chest, abdomen, and pelvis, and colorectal screening. Testing should also include measurement of serum and CSF autoantibodies associated with paraneoplastic cerebellar degeneration. The expanding list of paraneoplastic antibodies that may attack the cerebellum includes anti-Hu (often associated with small cell lung cancer), anti-Yo (associated with ovarian or breast cancer), anti-aquaporin 4, antibodies to the voltage-gated potassium channel, and anti–glutamic acid decarboxylase (anti-GAD).

Mammography and breast examination findings were normal. Computed tomography (CT) of the chest showed no adenopathy, nodules, or masses. Abdomen CT showed nonspecific prominence of the gallbladder wall. Flexible sigmoidoscopy revealed no masses, only thickened folds in the sigmoid colon; results of multiple colon biopsy tests were normal. Carcinoembryonic antigen level was 2.0 μg/L, and CA-125 level 5 U/mL. Serum GAD-65 antibodies were elevated (>30 nmol/L).

Anti-GAD is mostly known as the antibody associated with type 1 diabetes mellitus (T1DM). In rare instances, even in patients without a history of diabetes, anti-GAD antibodies may lead to an autoimmune attack on the brain, particularly the cerebellum, as part of an idiopathic autoimmune disorder or as a paraneoplastic syndrome. In either case, treatment involves corticosteroids, intravenous Ig, or plasma exchange. When the autoimmune attack is associated with malignancy, treatment response is poorer, unless the malignancy is successfully managed. The next steps are intravenous Ig or plasma exchange and positron emission tomography–CT (PET-CT) assessing for an underlying neoplasm that may have been too small to be detected with routine CT.

Numerous antibodies to antigens of the nervous system have been identified in association with malignancy, resulting in a variety of paraneoplastic neurologic syndromes (PNSs). Collectively, these syndromes are seen in fewer than 1 in 10,000 patients with cancer. The malignancy may be diagnosed months to years before the paraneoplastic syndrome, or the syndrome may be the first clue to underlying malignancy.¹ Hospitalists should suspect a PNS if the patient has known cancer and has unexplained neurologic deficits, if the presentation fits a classic PNS pattern, or if evaluation for neurologic symptoms identifies an inflammatory CSF profile that cannot be explained by demyelinating disorder or infection.

• The differential diagnosis for cerebellar deficits associated with normal brain MRI includes infection, toxic-metabolic insults (alcohol toxicity, vitamin B₁₂ deficiency, medication toxicity), anoxia, early neurodegenerative illness, and antibody-mediated disorders, such as autoimmune, postinfectious, and paraneoplastic syndromes.
• Hospitalists should suspect a PNS when a patient with known cancer develops unexplained neurologic deficits or when evaluation for neurologic symptoms identifies an inflammatory CSF profile that cannot be explained by a demyelinating disorder or an infection.
• Hospitalists should familiarize themselves with the classic PNS presentations, including limbic encephalitis, cerebellar degeneration, stiff person syndrome, opsoclonus-myoclonus, NMDA receptor encephalitis, and encephalomyelitis.
• Suspicion for PNS may be confirmed by the presence of paraneoplastic antibodies in CSF or serum. When routine evaluation fails to identify cancer, PET-CT should be performed.

Disclosure

Nothing to report.

The approach to clinical conundrums by an expert clinician is revealed through the presentation of an actual patient’s case in an approach typical of a morning report. Similarly to patient care, sequential pieces of information are provided to the clinician, who is unfamiliar with the case. The focus is on the thought processes of both the clinical team caring for the patient and the discussant.

A 78-year-old woman presented to her primary care physician with a 2-month history of progressive leg weakness. She reported walking difficulty caused by occasional “buckling” of the knees.

The knee buckling may be a clue to the quadriceps muscle weakness. The quadriceps straightens and locks the knee when the foot is being planted. Weakness of this muscle can result in the knee giving way. Isolated quadriceps weakness, which is uncommon, typically is caused by lower motor neuron issues, such as femoral neuropathy, L4–L5 radiculopathy, lumbosacral plexopathy, and primary muscle diseases, including inclusion body myositis.

The patient had diabetes mellitus and hypertension. Her medications were insulin glargine, metformin, glipizide, lisinopril, atorvastatin, and aspirin, and she was taking vitamin D and calcium. None of these was recently changed or added. Aside from having the weakness, the patient was in her usual state of health and had no other complaints. She denied weight changes, fevers, night sweats, and fatigue. She was widowed, lived with her daughter, had no pets, never used tobacco, and did not drink alcohol or use illicit drugs. There was no family history of neuromuscular disorders, and both of her parents died of natural causes at advanced ages.

The physical examination revealed no knee deformities, and the patient had good active range of motion of both knees and normal strength throughout her limbs. Plain radiographs of the knees showed mild medial compartment osteoarthritis. The patient was advised to stop atorvastatin.

Patients who take atorvastatin and other statins (3-hydroxy-3-methyl-glutaryl-co-enzyme A reductase inhibitors) can experience a spectrum of muscle disease, from myalgias and weakness to (rare) overt myositis with rhabdomyolysis. Statin-induced myopathy tends to affect larger proximal muscles, can occur at any time during the period the medication is being used, and usually resolves within weeks after discontinuation. Given this patient’s preserved strength, it was reasonable to manage her conservatively.

One month later, she presented to another hospital’s emergency department with increasing weakness in the lower extremities and new loss of balance requiring use of a walker for ambulation. She thought the weakness was confined to her legs and was affecting her thigh muscles more than her calves or feet. She reported fatigue, decreased appetite, and an unintentional 15-pound weight loss. She denied diarrhea, back pain, bowel and bladder function problems, sensation changes, myalgias, and arthralgias. She reported no swallowing or vision problems, rashes, Raynaud disease symptoms, photosensitivity, dry eyes or mouth, recent falls or trauma, fevers, night sweats, recent illness, or travel.

On physical examination, the patient’s temperature was 98.2°F, blood pressure 120/84 mm Hg, pulse 73 beats per minute, respiratory rate 16 breaths per minute, and oxygen saturation 99% with ambient air. The patient was obese and not in distress. She was alert, oriented, and able to follow multistep instructions. Cranial nerve examination was normal. The patient had mild weakness in her bilateral deltoids and bilateral hip flexors but full strength in all other muscle groups. Deep tendon reflexes were normal in the biceps and patella and reduced in the ankles. The Babinski sign was absent. Throughout the lower extremities, sensation was intact to light touch; there was no saddle anesthesia. Finger–nose–finger testing showed slight dysmetria in the left upper extremity. Because of her imbalance, the patient needed help to stand up; once upright, though, she was able to take 3 steps forward and backward with use of a walker. Her stride length was diminished, and her gait unsteady and wide based.

These exam findings suggest 2 separate localizations. Symmetric proximal weakness with preserved distal strength in the extremities indicate a lower motor neuron problem, further suggested by the absence of upper motor neuron findings of spasticity, and hyperreflexia. Intact patellar and biceps reflexes suggest either muscle or neuromuscular junction localization. Separately, the findings of wide-based gait and dysmetria raise the possibility of a problem in the ipsilateral cerebellum, in this case on the left. A cerebellar lesion would not explain the bilateral symmetric weakness. The combination of lower motor neuron leg weakness and cerebellar deficits suggests a systemic disorder, such as an infectious, inflammatory, or paraneoplastic process. A space-occupying lesion would not produce this constellation of deficits.

Serum chemistry panel was normal, creatinine level 0.47 mg/dL, and albumin level 4.0 g/dL. White blood cell (WBC) count was 8100/mm³, hemoglobin level 12 g/dL, and platelet count 287,000/mm³. Alanine aminotransferase (ALT) level was 74 U/L (reference range, 0-36 U/L), alkaline phosphatase level 41 U/L (reference range, 37-117 U/L), and total bilirubin level 0.4 mg/dL (reference range, 0.2-1.2 mg/dL). Prothrombin time and thyrotropin were normal. Creatine kinase (CK) level was 2328 U/L (reference range, <200 U/L). Erythrocyte sedimentation rate was 17 mm/h, and C-reactive protein level 0.1 mg/L. Urinalysis (dipstick testing) detected no myoglobin, and there were no casts. Plain radiograph of the chest was normal.

The elevated CK indicates muscle disease, and, in the absence of other findings of liver disease, the ALT elevation likely has a muscle origin as well. The differential diagnosis for elevated CK includes myopathy caused either by infection, trauma, ischemia, or a toxin (medication included) or by a hereditary, metabolic, endocrinologic, or inflammatory disorder. There is no history of trauma, strenuous exertion, or muscle toxin other than the statin, and the progression of symptoms after medication discontinuation argues against statin myopathy. The laboratory test results rule out derangement of potassium, calcium, phosphorus, magnesium, vitamin D, or thyroid function as the cause of the myopathy. The absence of fever, absence of diffuse organ involvement, and normal inflammatory markers point away from a systemic infection or vasculitis. The inflammatory myopathies dermatomyositis and polymyositis classically produce proximal muscle weakness and are possibilities in this case, but one would expect the inflammatory markers to be elevated in these conditions. Malignancy related to dermatomyositis or to paraneoplastic syndrome may account for the myopathy.

The data provided do not identify a unifying diagnosis. To look for an inflammatory myopathy, such as dermatomyositis or polymyositis, it is reasonable to perform electromyography (EMG) to delineate the location of muscle involvement and identify a site for tissue biopsy. As no obvious toxins or metabolic conditions explain the dysmetria, magnetic resonance imaging (MRI) of the brain should be performed to evaluate for lesions in the cerebellum.

The patient was admitted to the hospital. On T2-weighted and FLAIR (fluid attenuation inversion recovery) sequences, MRI of the brain showed a few scattered subcortical and periventricular white matter hyperintense foci bilaterally. Antibodies to human immunodeficiency virus 1 and 2, and Treponema pallidum immunoglobulins G and M, were not detected. Serum levels of lactate dehydrogenase, vitamin B ₁₂ , angiotensin-converting enzyme, antinuclear antibody, rheumatoid factor, and anti–cyclic citrullinated peptide IgG were normal.

The brain imaging excludes a space-occupying lesion in the cerebellum but does not identify the cause of dysmetria. Toxic-metabolic conditions, such as alcohol toxicity, vitamin B₁₂ deficiency, anoxia, and toxicity of certain medications, may impair cerebellar function (MRI findings may be normal), but none of these is present. Other disorders that attack the central nervous system (CNS) (again, brain imaging may show minimal abnormalities) include infections, early-stage neurodegenerative illnesses, and antibody-associated disorders (eg, autoimmune diseases, postinfectious and paraneoplastic conditions).

Four days after intravenous fluids were started, the patient’s CK level improved, but her weakness persisted. There was no evidence of peripheral neuropathy on lower extremity nerve conduction studies. EMG revealed few fibrillations and positive sharp waves in proximal limb muscles and thoracic paraspinal muscles. Deltoid, biceps, and tensor fasciae latae showed shorter duration complex motor units with early recruitment. The patient declined muscle biopsy. A rheumatologist was consulted, and prednisone 60 mg/d was started for possible inflammatory myopathy. The patient was discharged to a skilled nursing facility for physical therapy.

The fibrillations and positive sharp waves on EMG can be seen in both neuropathy (from denervation) and myopathy. The normal nerve conduction studies make localization to the nerve unlikely. In addition, the shorter duration motor units with early recruitment on EMG are characteristic of a myopathy. Despite the ongoing myopathy, the improved CK level suggests the muscle disease is playing a minimal role in the patient’s current illness. Prescribing corticosteroids for a presumed inflammatory myopathy without a clear diagnosis is risky, as steroids may render subsequent biopsy results unreliable, may themselves cause myopathy, and expose the patient to the side effects of immunosuppression.

One month later, the patient saw her rheumatologist. Although she had tapered the prednisone down to 10 mg/d, she had not returned to baseline strength, was still using a walker, and reported increased difficulty keeping her head raised. She also noted 2 new symptoms: speech slurring and, in both hands, a tremor that made it difficult to hold objects.

Examination revealed a fine tremor in both arms. There were no skin lesions, and the joints were normal. The patient was oriented to name, place, and date. Memory testing was 3 for 3 on register but 0 for 3 on recall. She was unable to perform serial 7s and able to spell backward only 3 of the 5 letters in the word world . Speech was dysarthric and scanning in quality. On extraocular movements, she demonstrated poor smooth pursuit. Examination of the head and neck was significant for nearly constant head titubation and weak neck flexors. Upper extremity strength was normal. Mild weakness was noted in both hip flexors. Deep tendon reflexes were preserved except at the ankle, where they were reduced. Finger–nose–finger testing revealed marked dysmetria, more pronounced on the left, and there was mild bilateral heel-to-shin dysmetria.

Diffuse myopathy cannot account for the patient’s impaired cognition or progressive cerebellar findings, which now include head titubation and scanning speech. As more than a month has elapsed since the brain imaging was performed, MRI could be repeated for evidence of infection, malignancy, inflammation, or demyelination. More important, lumbar puncture is indicated to exclude infection and, with flow cytometry, cytology, and measurement of oligoclonal bands and IgG index, to assess for autoimmune or paraneoplastic antibody-mediated disorders.

The patient was readmitted. On repeat brain MRI, there were no new significant findings. Complete blood cell count and chemistry panel results were unremarkable. Erythrocyte sedimentation rate and C-reactive protein level remained normal. CK level was 451 U/L, and ALT level 29 U/L.

Lumbar puncture was performed. Opening pressure was 14.5 cm of water, and cerebrospinal fluid (CSF) was clear and colorless. There were 3 red blood cells/mm ³ and no WBCs. Glucose level was 94 mg/dL, and protein level 74 mg/dL. CSF IgG synthesis rate was normal, flow cytometry revealed no abnormal clonal populations, and cytology was negative for malignancy. Two unique oligoclonal bands were found in the CSF.

The absence of WBCs in the CSF excludes CNS infection. The patient’s main problem is an inflammatory CNS process as defined by presence of oligoclonal bands in the CSF, compared with their absence in the serum. Autoimmune, neoplastic, and paraneoplastic disorders could explain these bands. There was no evidence of systemic autoimmune illness. The patient has not had a recent infection that could result in postinfectious demyelination, and her clinical and imaging features are not suggestive of a demyelinating disorder, such as multiple sclerosis. Of the neoplastic possibilities, lymphoma with CNS involvement may be difficult to detect initially; this diagnosis, however, is not supported by the unremarkable MRI, flow cytometry, and cytology findings. In paraneoplastic syndromes, the CSF may include antibodies that react to antigens in the brain or cerebellum.

At this point, evaluation for malignancy should involve mammography, imaging of the chest, abdomen, and pelvis, and colorectal screening. Testing should also include measurement of serum and CSF autoantibodies associated with paraneoplastic cerebellar degeneration. The expanding list of paraneoplastic antibodies that may attack the cerebellum includes anti-Hu (often associated with small cell lung cancer), anti-Yo (associated with ovarian or breast cancer), anti-aquaporin 4, antibodies to the voltage-gated potassium channel, and anti–glutamic acid decarboxylase (anti-GAD).

Mammography and breast examination findings were normal. Computed tomography (CT) of the chest showed no adenopathy, nodules, or masses. Abdomen CT showed nonspecific prominence of the gallbladder wall. Flexible sigmoidoscopy revealed no masses, only thickened folds in the sigmoid colon; results of multiple colon biopsy tests were normal. Carcinoembryonic antigen level was 2.0 μg/L, and CA-125 level 5 U/mL. Serum GAD-65 antibodies were elevated (>30 nmol/L).

Anti-GAD is mostly known as the antibody associated with type 1 diabetes mellitus (T1DM). In rare instances, even in patients without a history of diabetes, anti-GAD antibodies may lead to an autoimmune attack on the brain, particularly the cerebellum, as part of an idiopathic autoimmune disorder or as a paraneoplastic syndrome. In either case, treatment involves corticosteroids, intravenous Ig, or plasma exchange. When the autoimmune attack is associated with malignancy, treatment response is poorer, unless the malignancy is successfully managed. The next steps are intravenous Ig or plasma exchange and positron emission tomography–CT (PET-CT) assessing for an underlying neoplasm that may have been too small to be detected with routine CT.

Numerous antibodies to antigens of the nervous system have been identified in association with malignancy, resulting in a variety of paraneoplastic neurologic syndromes (PNSs). Collectively, these syndromes are seen in fewer than 1 in 10,000 patients with cancer. The malignancy may be diagnosed months to years before the paraneoplastic syndrome, or the syndrome may be the first clue to underlying malignancy.¹ Hospitalists should suspect a PNS if the patient has known cancer and has unexplained neurologic deficits, if the presentation fits a classic PNS pattern, or if evaluation for neurologic symptoms identifies an inflammatory CSF profile that cannot be explained by demyelinating disorder or infection.

• The differential diagnosis for cerebellar deficits associated with normal brain MRI includes infection, toxic-metabolic insults (alcohol toxicity, vitamin B₁₂ deficiency, medication toxicity), anoxia, early neurodegenerative illness, and antibody-mediated disorders, such as autoimmune, postinfectious, and paraneoplastic syndromes.
• Hospitalists should suspect a PNS when a patient with known cancer develops unexplained neurologic deficits or when evaluation for neurologic symptoms identifies an inflammatory CSF profile that cannot be explained by a demyelinating disorder or an infection.
• Hospitalists should familiarize themselves with the classic PNS presentations, including limbic encephalitis, cerebellar degeneration, stiff person syndrome, opsoclonus-myoclonus, NMDA receptor encephalitis, and encephalomyelitis.
• Suspicion for PNS may be confirmed by the presence of paraneoplastic antibodies in CSF or serum. When routine evaluation fails to identify cancer, PET-CT should be performed.

Disclosure

Nothing to report.

The approach to clinical conundrums by an expert clinician is revealed through the presentation of an actual patient’s case in an approach typical of a morning report. Similarly to patient care, sequential pieces of information are provided to the clinician, who is unfamiliar with the case. The focus is on the thought processes of both the clinical team caring for the patient and the discussant. The bolded text represents the patient’s case. Each paragraph that follows represents the discussant’s thoughts.

A 63-year-old man at an inpatient rehabilitation center was transferred to an academic tertiary care center for evaluation of slurred speech and episodic confusion. He was accompanied by his wife, who provided the history. Three weeks earlier, the patient had fallen, sustaining a right femur fracture. He underwent surgery and was discharged to rehabilitation on postoperative day 3. During the second week of rehabilitation, he developed a cough and low-grade fevers, which prompted treatment with cefpodoxime for 5 days for presumed pneumonia. The day after completing antimicrobial therapy, he became confused and began to slur his words.

Confusion is a nonspecific symptom that typically has a diffuse or multifocal localization within the cerebral hemispheres and is unlikely to be caused by a single lesion. Slurred speech may accompany global metabolic dysfunction. However, slurred speech typically localizes to the brainstem, the cerebellum in the posterior fossa, the nuclei, or the course of cranial nerves VII, X, or XII, including where these nerves pass through the subarachnoid space.

It seems this patient’s new neurologic symptoms have some relationship to his fall. Long-bone fractures and altered mental status (AMS) lead to consideration of fat emboli, but this syndrome typically presents in the acute period after the fracture. The patient is at risk for a number of complications, related to recent surgery and hospitalization, that could affect the central nervous system (CNS), including systemic infection (possibly with associated meningeal involvement) and venous thromboembolism with concomitant stroke by paradoxical emboli. The episodic nature of the confusion leads to consideration of seizures from structural lesions in the brain. Finally, the circumstances of the fall itself should be explored to determine whether an underlying neurologic dysfunction led to imbalance and gait difficulty.

Over the next 3 days at the inpatient rehabilitation center, the patient’s slurred speech became unintelligible, and he experienced intermittent disorientation to person, place, and time. There was no concomitant fever, dizziness, headache, neck pain, weakness, dyspnea, diarrhea, dysuria, or change in hearing or vision.

Progressive dysarthria argues for an expanding lesion in the posterior fossa, worsening metabolic disturbance, or a problem affecting the cranial nerves (eg, Guillain-Barré syndrome) or neuromuscular junctions (eg, myasthenia gravis). Lack of headache makes a CNS localization less likely, though disorientation must localize to the brain itself. The transient nature of the AMS could signal an ictal phenomenon or a fluctuating toxic or metabolic condition, such as hyperammonemia, drug reaction, or healthcare–acquired delirium.

His past medical history included end-stage liver disease secondary to nonalcoholic steatohepatitis status post transjugular intrahepatic portosystemic shunt (TIPS) procedure three years prior, hepatic encephalopathy, diabetes mellitus type 2, hypertension, previous melanoma excision on his back, and recurrent Clostridium difficile colitis. Two years prior to admission he had been started on an indefinite course of metronidazole 500 mg twice daily without any recurrence. The patient’s other medications were aspirin, furosemide, insulin, lactulose, mirtazapine, pantoprazole, propranolol, spironolactone, and zinc. At the rehabilitation center, he was prescribed oral oxycodone 5 mg as needed every 4 hours for pain. He denied use of tobacco, alcohol, and recreational drugs. He previously worked as a funeral home director and embalmer.

Hyperammonemia and hepatic encephalopathy can present with a fluctuating mental state that often correlates to dietary protein intake or the frequency of bowel movements; the previous TIPS history places the patient at further risk. Use of oxycodone or another narcotic commonly leads to confusion, , especially in patients who are older, have preexisting cognitive decline, or have concomitant medical comorbidities. Mirtazapine and propranolol have been associated more rarely with encephalopathy, and therefore a careful history of adherence, drug interactions, and appropriate dosing should be obtained. Metronidazole is most often associated neurologically with a peripheral neuropathy; however, it is increasingly recognized that some patients can develop a CNS syndrome that features an AMS, which can be severe and accompanied by ataxia, dysarthria, and characteristic brain magnetic resonance imaging (MRI) findings, including hyperintensity surrounding the fourth ventricle on T₂-weighted images.

Embalming fluid has a high concentration of formaldehyde, and a recent epidemiologic study suggested a link between formaldehyde exposure and increased risk for amyotrophic lateral sclerosis (ALS). ALS uncommonly presents with isolated dysarthria, but its bulbar form can, usually over a much longer course than is demonstrated here. Finally, the patient’s history of melanoma places him at risk for stroke from hypercoagulability as well as potential brain metastases or carcinomatous meningitis.

Evaluation was initiated at the rehabilitation facility at the onset of the patient’s slurred speech and confusion. Physical examination were negative for focal neurologic deficits, asterixis, and jaundice. Ammonia level was 41 µmol/L (reference range, 11-35 µmol/L). Noncontrast computed tomography (CT) of the head showed no signs of acute infarct or hemorrhage. Symptoms were attributed to hepatic encephalopathy; lactulose was up-titrated to ensure 2 or 3 bowel movements per day, and rifaximin was started.

Hyperammonemia is a cause of non-inflammatory relapsing encephalopathy, but an elevated level is neither a sensitive nor specific indicator of hepatic encephalopathy. Levels of ammonia can fluctuate widely during the day based on the frequency of bowel movements as well as dietary protein intake. In addition, proper handling of samples with prompt delivery to the laboratory is essential to minimize errors.

The ammonia level of 41 µmol/L discovered here is only modestly elevated, but given the patient’s history of TIPS as well as the clinical picture, it is reasonable to aggressively treat hepatic encephalopathy with lactulose to reduce ammonia levels. If he does not improve, an MRI of the brain to exclude a structural lesion and spinal fluid examination looking for inflammatory or infectious conditions would be important next steps. Although CT excludes a large hemorrhage or mass, this screening examination does not visualize many of the findings of the metabolic etiology and the other etiologies under consideration here.

Despite 3 days of therapy for presumed hepatic encephalopathy, the patient’s slurred speech worsened, and he was transferred to an academic tertiary care center for further evaluation. On admission, his temperature was 36.9°C, heart rate was 80 beats per minute, blood pressure was 139/67 mm Hg, respiratory rate was 10 breaths per minute, and oxygen saturation was 99% on room air. He was alert, awake, and oriented to person, place, and time. He was not jaundiced. He exhibited a moderate dysarthria characterized by monotone speech, decreased volume, decreased breath support, and a hoarse vocal quality with intact language function. Motor control of the lips, tongue, and mandible were normal. Motor strength was 5/5 bilaterally in the upper and lower extremities with the exception of right hip flexion, which was 4/5. The patient exhibited mild bilateral dysmetria on finger-to-nose examination, consistent with appendicular ataxia of the upper extremities. Reflexes were depressed throughout, and there was no asterixis. He had 2+ pulses in all extremities and 1+ pitting edema of the right lower extremity to the mid leg. Pulmonary examination revealed inspiratory crackles at the left base. The rest of the examination findings were normal.

The patient’s altered mental state appears to have resolved, and the neurological examination is now mainly characterized by signs that point to the cerebellum. The description of monotone speech typically refers to loss of prosody, the variable stress or intonation of speech, which is characteristic of a cerebellar speech pattern. The hoarseness should be explored to determine if it is a feature of the patient’s speech or is a separate process. Hoarseness may involve the vocal cord and therefore, potentially, cranial nerve X or its nuclei in the brainstem. The appendicular ataxia of the limbs points definitively to the cerebellar hemispheres or their pathways through the brainstem.

Unilateral lower extremity edema, especially in the context of a recent fracture, raises the possibility of deep vein thrombosis. If this patient has a right-to-left intracardiac or intrapulmonary shunt, embolization could lead to an ischemic stroke of the brainstem or cerebellum, potentially causing dysarthria.

Laboratory evaluation revealed hemoglobin level of 10.9 g/dL, white blood cell count of 5.3 × 10 ⁹ /L, platelet count of 169 × 10 ⁹ /L, glucose level of 177 mg/dL, corrected calcium level of 9.0 mg/dL, sodium level of 135 mmol/L, bicarbonate level of 30 mmol/L, creatinine level of 0.9 mg/dL, total bilirubin level of 1.3 mg/dL, direct bilirubin level of 0.4 mg/dL, alkaline phosphatase level of 503 U/L, alanine aminotransferase level of 12 U/L, aspartate aminotransferase level of 33 U/L, ammonia level of 49 µmol/L (range, 0-30 µ mol/L), international normalized ratio of 1.2, and troponin level of <0.01 ng/mL. Electrocardiogram showed normal sinus rhythm.

Some patients with bacterial meningitis do not have a leukocytosis, but patients with meningitis caused by seeding from a systemic infection nearly always do. In this patient’s case, lack of a leukocytosis makes bacterial meningitis very unlikely. The elevated alkaline phosphatase level is expected, as this level peaks about 3 weeks after a long-bone fracture and returns to normal over a few months.

Non-contrast CT scan of the head performed on admission demonstrated no large vessel cortical-based infarct, intracranial hemorrhage, hydrocephalus, mass effect, midline shift, or extra-axial fluid. There was mild cortical atrophy as well as very mild periventricular white matter hypodensity.

The atrophy and mild white-matter hypodensities seen on repeat noncontrast CT are nonspecific for any particular entity in this patient’s age group. MRI is more effective in evaluating toxic encephalopathies, including metronidazole toxicity or Wernicke encephalopathy, and in characterizing small infarcts or inflammatory conditions of the brainstem and cerebellum, which are poorly evaluated by CT due to the bone surrounded space of the posterior fossa. An urgent lumbar puncture is not necessary due to the slow pace of illness, lack of fever, nuchal rigidity, or serum elevated white blood cell count. Rather, performing MRI should be prioritized. If MRI is nondiagnostic, then spinal fluid should be evaluated for evidence of an infectious, autoimmune, paraneoplastic, or neoplastic process.

MRI was subsequently performed. It showed symmetric abnormal T₂ hyperintensities involving dentate nuclei (Figure 1), left inferior olivary nuclei (Figure 2), restiform bodies, pontine tegmentum, superior cerebellar peduncles, oculomotor nuclei, and subthalamic nuclei. The most prominent hyperintensity was in the dentate nuclei.

Metronidazole was originally developed in France during the 1950s as an anti-parasitic medication to treat trichomonas infections. In 1962, its antibacterial properties were discovered after a patient with bacterial gingivitis improved while taking metronidazole for treatment of Trichomonas vaginalis.¹ Since that time metronidazole has become a first-line treatment for anaerobic bacteria and is now recommended by the Infectious Diseases Society of America² and the American College of Gastroenterology³ as a first-line therapy for mild and moderate C difficile infections.

Common side effects of metronidazole are nausea, vomiting, decreased appetite, diarrhea, headaches, peripheral neuropathy, and metallic taste; less common is CNS toxicity. Although the incidence of CNS toxicity is unknown, a systematic review of the literature found 64 cases reported between 1965 and 2011.⁴ CNS toxicity most often occurs between the fifth and sixth decades of life, and about two thirds of the people affected are men.⁴ CNS adverse effects characteristically fall into 4 categories: cerebellar dysfunction (eg, ataxia, dysarthria, dysmetria, nystagmus; 75%), AMS (33%), seizures (13%), and a combination of the first 3 categories.⁴

The exact mechanism of metronidazole CNS toxicity is unknown, but vasogenic or cytotoxic edema may be involved.^5,6 Other potential etiologies are neural protein inhibition, reversible mitochondrial dysfunction, and modifications of the inhibitory neurotransmitter gamma-aminobutyric acid receptor in the cerebellum.^7,8 There is no known genetic predisposition. Although the risk for CNS toxicity traditionally is thought to correlate with therapy duration and cumulative dose,^7,9 in 2011 a systemic review found no significant correlation.⁴ In fact, 26% of patients with CNS toxicity were treated with metronidazole for less than 1 week at time of diagnosis.⁴

Brain CT is typically normal. On brain MRI, lesions most commonly appear as bilateral symmetric T₂ hyperintensities, most often in the cerebellar dentate nuclei (85%) and less often in the midbrain (55%), the splenium of the corpus callosum (50%), the pons (35%), and the medulla (30%).^4,10 Radiographic changes have been noted as early as 3 days after symptom onset. Based on damage severity and area affected (white or gray matter), vasogenic edema and cytotoxic edema may in combination be contributing to MRI abnormalities.^6,10 Hyperintensities of the bilateral dentate nuclei can help in distinguishing metronidazole-induced encephalopathy from other potential disease processes, such as Wernicke encephalopathy.¹⁰

The prognosis for patients with metronidazole-induced neurotoxicity is favorable if metronidazole is discontinued. Approximately two-thirds of patients will have complete resolution of symptoms, which is more commonly observed when patients present with seizures or altered mental status. Approximately one-third will show partial improvement, particularly if the symptoms are due to cerebellar dysfunction. It is rare to experience permanent damage or death.⁴ Neurologic recovery usually begins within a week after medication discontinuation but may take months for complete recovery to occur.^6,8,9,11 Follow-up imaging typically shows reversal of the original lesions, but this does not always correlate with symptom improvement.^4,10

Despite its frequent use and long history, metronidazole can have potentially severe toxicity. When patients who are taking this medication present with new signs and symptoms of CNS dysfunction, hospitalists should include metronidazole CNS toxicity in the differential diagnosis and, if they suspect toxicity, have a brain MRI performed. Hospitalists often prescribe metronidazole because of the increasing number of patients being discharged from acute-care hospitals with a diagnosis of C difficile colitis.¹² Brain MRI remains the imaging modality of choice for diagnosis. Discontinuation of metronidazole is usually salutary in reversing symptoms. Being keenly aware of this toxicity will help clinicians avoid being rendered speechless by a patient rendered speechless.

• CNS toxicity is a rare but potentially devastating side effect of metronidazole exposure.

• Metronidazole CNS adverse effects characteristically fall under 4 categories:

○ Cerebellar dysfunction, such as ataxia, dysarthria, dysmetria, or nystagmus (75%).

○ AMS (33%).

○ Seizures (13%).

○ A combination of the first 3 categories.

• Typically lesions indicating metronidazole toxicity on brain MRI are bilateral symmetric hyperintensities on T2-weighted imaging in the cerebellar dentate nuclei, corpus callosum, midbrain, pons, or medulla.
• Treatment of CNS toxicity is metronidazole discontinuation, which results in a high rate of symptom resolution.

Disclosure

Nothing to report.

The approach to clinical conundrums by an expert clinician is revealed through the presentation of an actual patient’s case in an approach typical of a morning report. Similarly to patient care, sequential pieces of information are provided to the clinician, who is unfamiliar with the case. The focus is on the thought processes of both the clinical team caring for the patient and the discussant. The bolded text represents the patient’s case. Each paragraph that follows represents the discussant’s thoughts.

A 63-year-old man at an inpatient rehabilitation center was transferred to an academic tertiary care center for evaluation of slurred speech and episodic confusion. He was accompanied by his wife, who provided the history. Three weeks earlier, the patient had fallen, sustaining a right femur fracture. He underwent surgery and was discharged to rehabilitation on postoperative day 3. During the second week of rehabilitation, he developed a cough and low-grade fevers, which prompted treatment with cefpodoxime for 5 days for presumed pneumonia. The day after completing antimicrobial therapy, he became confused and began to slur his words.

Confusion is a nonspecific symptom that typically has a diffuse or multifocal localization within the cerebral hemispheres and is unlikely to be caused by a single lesion. Slurred speech may accompany global metabolic dysfunction. However, slurred speech typically localizes to the brainstem, the cerebellum in the posterior fossa, the nuclei, or the course of cranial nerves VII, X, or XII, including where these nerves pass through the subarachnoid space.

It seems this patient’s new neurologic symptoms have some relationship to his fall. Long-bone fractures and altered mental status (AMS) lead to consideration of fat emboli, but this syndrome typically presents in the acute period after the fracture. The patient is at risk for a number of complications, related to recent surgery and hospitalization, that could affect the central nervous system (CNS), including systemic infection (possibly with associated meningeal involvement) and venous thromboembolism with concomitant stroke by paradoxical emboli. The episodic nature of the confusion leads to consideration of seizures from structural lesions in the brain. Finally, the circumstances of the fall itself should be explored to determine whether an underlying neurologic dysfunction led to imbalance and gait difficulty.

Over the next 3 days at the inpatient rehabilitation center, the patient’s slurred speech became unintelligible, and he experienced intermittent disorientation to person, place, and time. There was no concomitant fever, dizziness, headache, neck pain, weakness, dyspnea, diarrhea, dysuria, or change in hearing or vision.

Progressive dysarthria argues for an expanding lesion in the posterior fossa, worsening metabolic disturbance, or a problem affecting the cranial nerves (eg, Guillain-Barré syndrome) or neuromuscular junctions (eg, myasthenia gravis). Lack of headache makes a CNS localization less likely, though disorientation must localize to the brain itself. The transient nature of the AMS could signal an ictal phenomenon or a fluctuating toxic or metabolic condition, such as hyperammonemia, drug reaction, or healthcare–acquired delirium.

His past medical history included end-stage liver disease secondary to nonalcoholic steatohepatitis status post transjugular intrahepatic portosystemic shunt (TIPS) procedure three years prior, hepatic encephalopathy, diabetes mellitus type 2, hypertension, previous melanoma excision on his back, and recurrent Clostridium difficile colitis. Two years prior to admission he had been started on an indefinite course of metronidazole 500 mg twice daily without any recurrence. The patient’s other medications were aspirin, furosemide, insulin, lactulose, mirtazapine, pantoprazole, propranolol, spironolactone, and zinc. At the rehabilitation center, he was prescribed oral oxycodone 5 mg as needed every 4 hours for pain. He denied use of tobacco, alcohol, and recreational drugs. He previously worked as a funeral home director and embalmer.

Hyperammonemia and hepatic encephalopathy can present with a fluctuating mental state that often correlates to dietary protein intake or the frequency of bowel movements; the previous TIPS history places the patient at further risk. Use of oxycodone or another narcotic commonly leads to confusion, , especially in patients who are older, have preexisting cognitive decline, or have concomitant medical comorbidities. Mirtazapine and propranolol have been associated more rarely with encephalopathy, and therefore a careful history of adherence, drug interactions, and appropriate dosing should be obtained. Metronidazole is most often associated neurologically with a peripheral neuropathy; however, it is increasingly recognized that some patients can develop a CNS syndrome that features an AMS, which can be severe and accompanied by ataxia, dysarthria, and characteristic brain magnetic resonance imaging (MRI) findings, including hyperintensity surrounding the fourth ventricle on T₂-weighted images.

Embalming fluid has a high concentration of formaldehyde, and a recent epidemiologic study suggested a link between formaldehyde exposure and increased risk for amyotrophic lateral sclerosis (ALS). ALS uncommonly presents with isolated dysarthria, but its bulbar form can, usually over a much longer course than is demonstrated here. Finally, the patient’s history of melanoma places him at risk for stroke from hypercoagulability as well as potential brain metastases or carcinomatous meningitis.

Evaluation was initiated at the rehabilitation facility at the onset of the patient’s slurred speech and confusion. Physical examination were negative for focal neurologic deficits, asterixis, and jaundice. Ammonia level was 41 µmol/L (reference range, 11-35 µmol/L). Noncontrast computed tomography (CT) of the head showed no signs of acute infarct or hemorrhage. Symptoms were attributed to hepatic encephalopathy; lactulose was up-titrated to ensure 2 or 3 bowel movements per day, and rifaximin was started.

Hyperammonemia is a cause of non-inflammatory relapsing encephalopathy, but an elevated level is neither a sensitive nor specific indicator of hepatic encephalopathy. Levels of ammonia can fluctuate widely during the day based on the frequency of bowel movements as well as dietary protein intake. In addition, proper handling of samples with prompt delivery to the laboratory is essential to minimize errors.

The ammonia level of 41 µmol/L discovered here is only modestly elevated, but given the patient’s history of TIPS as well as the clinical picture, it is reasonable to aggressively treat hepatic encephalopathy with lactulose to reduce ammonia levels. If he does not improve, an MRI of the brain to exclude a structural lesion and spinal fluid examination looking for inflammatory or infectious conditions would be important next steps. Although CT excludes a large hemorrhage or mass, this screening examination does not visualize many of the findings of the metabolic etiology and the other etiologies under consideration here.

Despite 3 days of therapy for presumed hepatic encephalopathy, the patient’s slurred speech worsened, and he was transferred to an academic tertiary care center for further evaluation. On admission, his temperature was 36.9°C, heart rate was 80 beats per minute, blood pressure was 139/67 mm Hg, respiratory rate was 10 breaths per minute, and oxygen saturation was 99% on room air. He was alert, awake, and oriented to person, place, and time. He was not jaundiced. He exhibited a moderate dysarthria characterized by monotone speech, decreased volume, decreased breath support, and a hoarse vocal quality with intact language function. Motor control of the lips, tongue, and mandible were normal. Motor strength was 5/5 bilaterally in the upper and lower extremities with the exception of right hip flexion, which was 4/5. The patient exhibited mild bilateral dysmetria on finger-to-nose examination, consistent with appendicular ataxia of the upper extremities. Reflexes were depressed throughout, and there was no asterixis. He had 2+ pulses in all extremities and 1+ pitting edema of the right lower extremity to the mid leg. Pulmonary examination revealed inspiratory crackles at the left base. The rest of the examination findings were normal.

The patient’s altered mental state appears to have resolved, and the neurological examination is now mainly characterized by signs that point to the cerebellum. The description of monotone speech typically refers to loss of prosody, the variable stress or intonation of speech, which is characteristic of a cerebellar speech pattern. The hoarseness should be explored to determine if it is a feature of the patient’s speech or is a separate process. Hoarseness may involve the vocal cord and therefore, potentially, cranial nerve X or its nuclei in the brainstem. The appendicular ataxia of the limbs points definitively to the cerebellar hemispheres or their pathways through the brainstem.

Unilateral lower extremity edema, especially in the context of a recent fracture, raises the possibility of deep vein thrombosis. If this patient has a right-to-left intracardiac or intrapulmonary shunt, embolization could lead to an ischemic stroke of the brainstem or cerebellum, potentially causing dysarthria.

Laboratory evaluation revealed hemoglobin level of 10.9 g/dL, white blood cell count of 5.3 × 10 ⁹ /L, platelet count of 169 × 10 ⁹ /L, glucose level of 177 mg/dL, corrected calcium level of 9.0 mg/dL, sodium level of 135 mmol/L, bicarbonate level of 30 mmol/L, creatinine level of 0.9 mg/dL, total bilirubin level of 1.3 mg/dL, direct bilirubin level of 0.4 mg/dL, alkaline phosphatase level of 503 U/L, alanine aminotransferase level of 12 U/L, aspartate aminotransferase level of 33 U/L, ammonia level of 49 µmol/L (range, 0-30 µ mol/L), international normalized ratio of 1.2, and troponin level of <0.01 ng/mL. Electrocardiogram showed normal sinus rhythm.

Some patients with bacterial meningitis do not have a leukocytosis, but patients with meningitis caused by seeding from a systemic infection nearly always do. In this patient’s case, lack of a leukocytosis makes bacterial meningitis very unlikely. The elevated alkaline phosphatase level is expected, as this level peaks about 3 weeks after a long-bone fracture and returns to normal over a few months.

Non-contrast CT scan of the head performed on admission demonstrated no large vessel cortical-based infarct, intracranial hemorrhage, hydrocephalus, mass effect, midline shift, or extra-axial fluid. There was mild cortical atrophy as well as very mild periventricular white matter hypodensity.

The atrophy and mild white-matter hypodensities seen on repeat noncontrast CT are nonspecific for any particular entity in this patient’s age group. MRI is more effective in evaluating toxic encephalopathies, including metronidazole toxicity or Wernicke encephalopathy, and in characterizing small infarcts or inflammatory conditions of the brainstem and cerebellum, which are poorly evaluated by CT due to the bone surrounded space of the posterior fossa. An urgent lumbar puncture is not necessary due to the slow pace of illness, lack of fever, nuchal rigidity, or serum elevated white blood cell count. Rather, performing MRI should be prioritized. If MRI is nondiagnostic, then spinal fluid should be evaluated for evidence of an infectious, autoimmune, paraneoplastic, or neoplastic process.

MRI was subsequently performed. It showed symmetric abnormal T₂ hyperintensities involving dentate nuclei (Figure 1), left inferior olivary nuclei (Figure 2), restiform bodies, pontine tegmentum, superior cerebellar peduncles, oculomotor nuclei, and subthalamic nuclei. The most prominent hyperintensity was in the dentate nuclei.

Metronidazole was originally developed in France during the 1950s as an anti-parasitic medication to treat trichomonas infections. In 1962, its antibacterial properties were discovered after a patient with bacterial gingivitis improved while taking metronidazole for treatment of Trichomonas vaginalis.¹ Since that time metronidazole has become a first-line treatment for anaerobic bacteria and is now recommended by the Infectious Diseases Society of America² and the American College of Gastroenterology³ as a first-line therapy for mild and moderate C difficile infections.

Common side effects of metronidazole are nausea, vomiting, decreased appetite, diarrhea, headaches, peripheral neuropathy, and metallic taste; less common is CNS toxicity. Although the incidence of CNS toxicity is unknown, a systematic review of the literature found 64 cases reported between 1965 and 2011.⁴ CNS toxicity most often occurs between the fifth and sixth decades of life, and about two thirds of the people affected are men.⁴ CNS adverse effects characteristically fall into 4 categories: cerebellar dysfunction (eg, ataxia, dysarthria, dysmetria, nystagmus; 75%), AMS (33%), seizures (13%), and a combination of the first 3 categories.⁴

The exact mechanism of metronidazole CNS toxicity is unknown, but vasogenic or cytotoxic edema may be involved.^5,6 Other potential etiologies are neural protein inhibition, reversible mitochondrial dysfunction, and modifications of the inhibitory neurotransmitter gamma-aminobutyric acid receptor in the cerebellum.^7,8 There is no known genetic predisposition. Although the risk for CNS toxicity traditionally is thought to correlate with therapy duration and cumulative dose,^7,9 in 2011 a systemic review found no significant correlation.⁴ In fact, 26% of patients with CNS toxicity were treated with metronidazole for less than 1 week at time of diagnosis.⁴

Brain CT is typically normal. On brain MRI, lesions most commonly appear as bilateral symmetric T₂ hyperintensities, most often in the cerebellar dentate nuclei (85%) and less often in the midbrain (55%), the splenium of the corpus callosum (50%), the pons (35%), and the medulla (30%).^4,10 Radiographic changes have been noted as early as 3 days after symptom onset. Based on damage severity and area affected (white or gray matter), vasogenic edema and cytotoxic edema may in combination be contributing to MRI abnormalities.^6,10 Hyperintensities of the bilateral dentate nuclei can help in distinguishing metronidazole-induced encephalopathy from other potential disease processes, such as Wernicke encephalopathy.¹⁰

The prognosis for patients with metronidazole-induced neurotoxicity is favorable if metronidazole is discontinued. Approximately two-thirds of patients will have complete resolution of symptoms, which is more commonly observed when patients present with seizures or altered mental status. Approximately one-third will show partial improvement, particularly if the symptoms are due to cerebellar dysfunction. It is rare to experience permanent damage or death.⁴ Neurologic recovery usually begins within a week after medication discontinuation but may take months for complete recovery to occur.^6,8,9,11 Follow-up imaging typically shows reversal of the original lesions, but this does not always correlate with symptom improvement.^4,10

Despite its frequent use and long history, metronidazole can have potentially severe toxicity. When patients who are taking this medication present with new signs and symptoms of CNS dysfunction, hospitalists should include metronidazole CNS toxicity in the differential diagnosis and, if they suspect toxicity, have a brain MRI performed. Hospitalists often prescribe metronidazole because of the increasing number of patients being discharged from acute-care hospitals with a diagnosis of C difficile colitis.¹² Brain MRI remains the imaging modality of choice for diagnosis. Discontinuation of metronidazole is usually salutary in reversing symptoms. Being keenly aware of this toxicity will help clinicians avoid being rendered speechless by a patient rendered speechless.

• CNS toxicity is a rare but potentially devastating side effect of metronidazole exposure.

• Metronidazole CNS adverse effects characteristically fall under 4 categories:

○ Cerebellar dysfunction, such as ataxia, dysarthria, dysmetria, or nystagmus (75%).

○ AMS (33%).

○ Seizures (13%).

○ A combination of the first 3 categories.

• Typically lesions indicating metronidazole toxicity on brain MRI are bilateral symmetric hyperintensities on T2-weighted imaging in the cerebellar dentate nuclei, corpus callosum, midbrain, pons, or medulla.
• Treatment of CNS toxicity is metronidazole discontinuation, which results in a high rate of symptom resolution.

Disclosure

Nothing to report.

The approach to clinical conundrums by an expert clinician is revealed through the presentation of an actual patient’s case in an approach typical of a morning report. Similarly to patient care, sequential pieces of information are provided to the clinician, who is unfamiliar with the case. The focus is on the thought processes of both the clinical team caring for the patient and the discussant. The bolded text represents the patient’s case. Each paragraph that follows represents the discussant’s thoughts.

A 63-year-old man at an inpatient rehabilitation center was transferred to an academic tertiary care center for evaluation of slurred speech and episodic confusion. He was accompanied by his wife, who provided the history. Three weeks earlier, the patient had fallen, sustaining a right femur fracture. He underwent surgery and was discharged to rehabilitation on postoperative day 3. During the second week of rehabilitation, he developed a cough and low-grade fevers, which prompted treatment with cefpodoxime for 5 days for presumed pneumonia. The day after completing antimicrobial therapy, he became confused and began to slur his words.

Confusion is a nonspecific symptom that typically has a diffuse or multifocal localization within the cerebral hemispheres and is unlikely to be caused by a single lesion. Slurred speech may accompany global metabolic dysfunction. However, slurred speech typically localizes to the brainstem, the cerebellum in the posterior fossa, the nuclei, or the course of cranial nerves VII, X, or XII, including where these nerves pass through the subarachnoid space.

It seems this patient’s new neurologic symptoms have some relationship to his fall. Long-bone fractures and altered mental status (AMS) lead to consideration of fat emboli, but this syndrome typically presents in the acute period after the fracture. The patient is at risk for a number of complications, related to recent surgery and hospitalization, that could affect the central nervous system (CNS), including systemic infection (possibly with associated meningeal involvement) and venous thromboembolism with concomitant stroke by paradoxical emboli. The episodic nature of the confusion leads to consideration of seizures from structural lesions in the brain. Finally, the circumstances of the fall itself should be explored to determine whether an underlying neurologic dysfunction led to imbalance and gait difficulty.

Over the next 3 days at the inpatient rehabilitation center, the patient’s slurred speech became unintelligible, and he experienced intermittent disorientation to person, place, and time. There was no concomitant fever, dizziness, headache, neck pain, weakness, dyspnea, diarrhea, dysuria, or change in hearing or vision.

Progressive dysarthria argues for an expanding lesion in the posterior fossa, worsening metabolic disturbance, or a problem affecting the cranial nerves (eg, Guillain-Barré syndrome) or neuromuscular junctions (eg, myasthenia gravis). Lack of headache makes a CNS localization less likely, though disorientation must localize to the brain itself. The transient nature of the AMS could signal an ictal phenomenon or a fluctuating toxic or metabolic condition, such as hyperammonemia, drug reaction, or healthcare–acquired delirium.

His past medical history included end-stage liver disease secondary to nonalcoholic steatohepatitis status post transjugular intrahepatic portosystemic shunt (TIPS) procedure three years prior, hepatic encephalopathy, diabetes mellitus type 2, hypertension, previous melanoma excision on his back, and recurrent Clostridium difficile colitis. Two years prior to admission he had been started on an indefinite course of metronidazole 500 mg twice daily without any recurrence. The patient’s other medications were aspirin, furosemide, insulin, lactulose, mirtazapine, pantoprazole, propranolol, spironolactone, and zinc. At the rehabilitation center, he was prescribed oral oxycodone 5 mg as needed every 4 hours for pain. He denied use of tobacco, alcohol, and recreational drugs. He previously worked as a funeral home director and embalmer.

Hyperammonemia and hepatic encephalopathy can present with a fluctuating mental state that often correlates to dietary protein intake or the frequency of bowel movements; the previous TIPS history places the patient at further risk. Use of oxycodone or another narcotic commonly leads to confusion, , especially in patients who are older, have preexisting cognitive decline, or have concomitant medical comorbidities. Mirtazapine and propranolol have been associated more rarely with encephalopathy, and therefore a careful history of adherence, drug interactions, and appropriate dosing should be obtained. Metronidazole is most often associated neurologically with a peripheral neuropathy; however, it is increasingly recognized that some patients can develop a CNS syndrome that features an AMS, which can be severe and accompanied by ataxia, dysarthria, and characteristic brain magnetic resonance imaging (MRI) findings, including hyperintensity surrounding the fourth ventricle on T₂-weighted images.

Embalming fluid has a high concentration of formaldehyde, and a recent epidemiologic study suggested a link between formaldehyde exposure and increased risk for amyotrophic lateral sclerosis (ALS). ALS uncommonly presents with isolated dysarthria, but its bulbar form can, usually over a much longer course than is demonstrated here. Finally, the patient’s history of melanoma places him at risk for stroke from hypercoagulability as well as potential brain metastases or carcinomatous meningitis.

Evaluation was initiated at the rehabilitation facility at the onset of the patient’s slurred speech and confusion. Physical examination were negative for focal neurologic deficits, asterixis, and jaundice. Ammonia level was 41 µmol/L (reference range, 11-35 µmol/L). Noncontrast computed tomography (CT) of the head showed no signs of acute infarct or hemorrhage. Symptoms were attributed to hepatic encephalopathy; lactulose was up-titrated to ensure 2 or 3 bowel movements per day, and rifaximin was started.

Hyperammonemia is a cause of non-inflammatory relapsing encephalopathy, but an elevated level is neither a sensitive nor specific indicator of hepatic encephalopathy. Levels of ammonia can fluctuate widely during the day based on the frequency of bowel movements as well as dietary protein intake. In addition, proper handling of samples with prompt delivery to the laboratory is essential to minimize errors.

The ammonia level of 41 µmol/L discovered here is only modestly elevated, but given the patient’s history of TIPS as well as the clinical picture, it is reasonable to aggressively treat hepatic encephalopathy with lactulose to reduce ammonia levels. If he does not improve, an MRI of the brain to exclude a structural lesion and spinal fluid examination looking for inflammatory or infectious conditions would be important next steps. Although CT excludes a large hemorrhage or mass, this screening examination does not visualize many of the findings of the metabolic etiology and the other etiologies under consideration here.

Despite 3 days of therapy for presumed hepatic encephalopathy, the patient’s slurred speech worsened, and he was transferred to an academic tertiary care center for further evaluation. On admission, his temperature was 36.9°C, heart rate was 80 beats per minute, blood pressure was 139/67 mm Hg, respiratory rate was 10 breaths per minute, and oxygen saturation was 99% on room air. He was alert, awake, and oriented to person, place, and time. He was not jaundiced. He exhibited a moderate dysarthria characterized by monotone speech, decreased volume, decreased breath support, and a hoarse vocal quality with intact language function. Motor control of the lips, tongue, and mandible were normal. Motor strength was 5/5 bilaterally in the upper and lower extremities with the exception of right hip flexion, which was 4/5. The patient exhibited mild bilateral dysmetria on finger-to-nose examination, consistent with appendicular ataxia of the upper extremities. Reflexes were depressed throughout, and there was no asterixis. He had 2+ pulses in all extremities and 1+ pitting edema of the right lower extremity to the mid leg. Pulmonary examination revealed inspiratory crackles at the left base. The rest of the examination findings were normal.

The patient’s altered mental state appears to have resolved, and the neurological examination is now mainly characterized by signs that point to the cerebellum. The description of monotone speech typically refers to loss of prosody, the variable stress or intonation of speech, which is characteristic of a cerebellar speech pattern. The hoarseness should be explored to determine if it is a feature of the patient’s speech or is a separate process. Hoarseness may involve the vocal cord and therefore, potentially, cranial nerve X or its nuclei in the brainstem. The appendicular ataxia of the limbs points definitively to the cerebellar hemispheres or their pathways through the brainstem.

Unilateral lower extremity edema, especially in the context of a recent fracture, raises the possibility of deep vein thrombosis. If this patient has a right-to-left intracardiac or intrapulmonary shunt, embolization could lead to an ischemic stroke of the brainstem or cerebellum, potentially causing dysarthria.

Laboratory evaluation revealed hemoglobin level of 10.9 g/dL, white blood cell count of 5.3 × 10 ⁹ /L, platelet count of 169 × 10 ⁹ /L, glucose level of 177 mg/dL, corrected calcium level of 9.0 mg/dL, sodium level of 135 mmol/L, bicarbonate level of 30 mmol/L, creatinine level of 0.9 mg/dL, total bilirubin level of 1.3 mg/dL, direct bilirubin level of 0.4 mg/dL, alkaline phosphatase level of 503 U/L, alanine aminotransferase level of 12 U/L, aspartate aminotransferase level of 33 U/L, ammonia level of 49 µmol/L (range, 0-30 µ mol/L), international normalized ratio of 1.2, and troponin level of <0.01 ng/mL. Electrocardiogram showed normal sinus rhythm.

Some patients with bacterial meningitis do not have a leukocytosis, but patients with meningitis caused by seeding from a systemic infection nearly always do. In this patient’s case, lack of a leukocytosis makes bacterial meningitis very unlikely. The elevated alkaline phosphatase level is expected, as this level peaks about 3 weeks after a long-bone fracture and returns to normal over a few months.

Non-contrast CT scan of the head performed on admission demonstrated no large vessel cortical-based infarct, intracranial hemorrhage, hydrocephalus, mass effect, midline shift, or extra-axial fluid. There was mild cortical atrophy as well as very mild periventricular white matter hypodensity.

The atrophy and mild white-matter hypodensities seen on repeat noncontrast CT are nonspecific for any particular entity in this patient’s age group. MRI is more effective in evaluating toxic encephalopathies, including metronidazole toxicity or Wernicke encephalopathy, and in characterizing small infarcts or inflammatory conditions of the brainstem and cerebellum, which are poorly evaluated by CT due to the bone surrounded space of the posterior fossa. An urgent lumbar puncture is not necessary due to the slow pace of illness, lack of fever, nuchal rigidity, or serum elevated white blood cell count. Rather, performing MRI should be prioritized. If MRI is nondiagnostic, then spinal fluid should be evaluated for evidence of an infectious, autoimmune, paraneoplastic, or neoplastic process.

MRI was subsequently performed. It showed symmetric abnormal T₂ hyperintensities involving dentate nuclei (Figure 1), left inferior olivary nuclei (Figure 2), restiform bodies, pontine tegmentum, superior cerebellar peduncles, oculomotor nuclei, and subthalamic nuclei. The most prominent hyperintensity was in the dentate nuclei.

Metronidazole was originally developed in France during the 1950s as an anti-parasitic medication to treat trichomonas infections. In 1962, its antibacterial properties were discovered after a patient with bacterial gingivitis improved while taking metronidazole for treatment of Trichomonas vaginalis.¹ Since that time metronidazole has become a first-line treatment for anaerobic bacteria and is now recommended by the Infectious Diseases Society of America² and the American College of Gastroenterology³ as a first-line therapy for mild and moderate C difficile infections.

Common side effects of metronidazole are nausea, vomiting, decreased appetite, diarrhea, headaches, peripheral neuropathy, and metallic taste; less common is CNS toxicity. Although the incidence of CNS toxicity is unknown, a systematic review of the literature found 64 cases reported between 1965 and 2011.⁴ CNS toxicity most often occurs between the fifth and sixth decades of life, and about two thirds of the people affected are men.⁴ CNS adverse effects characteristically fall into 4 categories: cerebellar dysfunction (eg, ataxia, dysarthria, dysmetria, nystagmus; 75%), AMS (33%), seizures (13%), and a combination of the first 3 categories.⁴

The exact mechanism of metronidazole CNS toxicity is unknown, but vasogenic or cytotoxic edema may be involved.^5,6 Other potential etiologies are neural protein inhibition, reversible mitochondrial dysfunction, and modifications of the inhibitory neurotransmitter gamma-aminobutyric acid receptor in the cerebellum.^7,8 There is no known genetic predisposition. Although the risk for CNS toxicity traditionally is thought to correlate with therapy duration and cumulative dose,^7,9 in 2011 a systemic review found no significant correlation.⁴ In fact, 26% of patients with CNS toxicity were treated with metronidazole for less than 1 week at time of diagnosis.⁴

Brain CT is typically normal. On brain MRI, lesions most commonly appear as bilateral symmetric T₂ hyperintensities, most often in the cerebellar dentate nuclei (85%) and less often in the midbrain (55%), the splenium of the corpus callosum (50%), the pons (35%), and the medulla (30%).^4,10 Radiographic changes have been noted as early as 3 days after symptom onset. Based on damage severity and area affected (white or gray matter), vasogenic edema and cytotoxic edema may in combination be contributing to MRI abnormalities.^6,10 Hyperintensities of the bilateral dentate nuclei can help in distinguishing metronidazole-induced encephalopathy from other potential disease processes, such as Wernicke encephalopathy.¹⁰

The prognosis for patients with metronidazole-induced neurotoxicity is favorable if metronidazole is discontinued. Approximately two-thirds of patients will have complete resolution of symptoms, which is more commonly observed when patients present with seizures or altered mental status. Approximately one-third will show partial improvement, particularly if the symptoms are due to cerebellar dysfunction. It is rare to experience permanent damage or death.⁴ Neurologic recovery usually begins within a week after medication discontinuation but may take months for complete recovery to occur.^6,8,9,11 Follow-up imaging typically shows reversal of the original lesions, but this does not always correlate with symptom improvement.^4,10

Despite its frequent use and long history, metronidazole can have potentially severe toxicity. When patients who are taking this medication present with new signs and symptoms of CNS dysfunction, hospitalists should include metronidazole CNS toxicity in the differential diagnosis and, if they suspect toxicity, have a brain MRI performed. Hospitalists often prescribe metronidazole because of the increasing number of patients being discharged from acute-care hospitals with a diagnosis of C difficile colitis.¹² Brain MRI remains the imaging modality of choice for diagnosis. Discontinuation of metronidazole is usually salutary in reversing symptoms. Being keenly aware of this toxicity will help clinicians avoid being rendered speechless by a patient rendered speechless.

• CNS toxicity is a rare but potentially devastating side effect of metronidazole exposure.

• Metronidazole CNS adverse effects characteristically fall under 4 categories:

○ Cerebellar dysfunction, such as ataxia, dysarthria, dysmetria, or nystagmus (75%).

○ AMS (33%).

○ Seizures (13%).

○ A combination of the first 3 categories.

• Typically lesions indicating metronidazole toxicity on brain MRI are bilateral symmetric hyperintensities on T2-weighted imaging in the cerebellar dentate nuclei, corpus callosum, midbrain, pons, or medulla.
• Treatment of CNS toxicity is metronidazole discontinuation, which results in a high rate of symptom resolution.

Disclosure

Nothing to report.

Neurologic emergencies such as acute stroke, status epilepticus, subarachnoid hemorrhage, neuromuscular weakness, and spinal cord injury affect millions of Americans yearly.^1,2 These conditions can be difficult to diagnose, and delays in recognition and treatment can have devastating results. Consequently, it is important for nonneurologists to be able to quickly recognize these conditions and initiate timely management, often while awaiting neurologic consultation.

Here, we review how to recognize and treat these common, serious conditions.

ACUTE ISCHEMIC STROKE: TIME IS OF THE ESSENCE

Stroke is the fourth leading cause of death in the United States and is one of the most common causes of disability worldwide.^3–5 About 85% of strokes are ischemic, resulting from diminished vascular supply to the brain. Symptoms such as facial droop, unilateral weakness or numbness, aphasia, gaze deviation, and unsteadiness of gait may be seen. Time is of the essence, as all currently available interventions are safe and effective only within defined time windows.

Diagnosis and assessment

When acute ischemic stroke is suspected, the clinical history, time of onset, and basic neurologic examination should be obtained quickly.

The National Institutes of Health (NIH) stroke scale is an objective marker for assessing stroke severity as well as evolution of disease and should be obtained in all stroke patients. Scores range from 0 (best) to 42 (worst) (www.ninds.nih.gov/doctors/NIH_Stroke_Scale.pdf).

Time of onset of symptoms is essential to determine, since it guides eligibility for acute therapies. Clinicians should ascertain the last time the patient was seen to be neurologically well in order to estimate this time window as closely as possible.

Laboratory tests should include a fingerstick blood glucose measurement, coagulation studies, complete blood cell count, and basic metabolic profile.

Computed tomography (CT) of the head without contrast should be obtained immediately to exclude acute hemorrhage and any alternative diagnoses that could explain the patient’s symptoms. Acute brain ischemia is often not apparent on CT during the first few hours of injury. Therefore, a patient presenting with new focal neurologic deficits and an unremarkable result on CT of the head should be treated as having had an acute ischemic stroke, and interventional therapies should be considered.

Stroke mimics should be considered and treated, as appropriate (Table 1).

Acute management of ischemic stroke

Acute treatment should not be delayed by obtaining chest radiography, inserting a Foley catheter, or obtaining an electrocardiogram. The longer the time that elapses before treatment, the worse the functional outcome, underscoring the need for rapid decision-making.^6–8

Lowering the head of the bed may provide benefit by promoting blood flow to ischemic brain tissue.⁹ However, this should not be done in patients with significantly elevated intracerebral pressure and concern for herniation.

Permissive hypertension (antihypertensive treatment only for blood pressure greater than 220/110 mm Hg) should be allowed per national guidelines to provide adequate perfusion to brain areas at risk of injury.¹⁰

Tissue plasminogen activator. Patients with ischemic stroke who present within 3 hours of symptom onset should be considered for intravenous administration of tissue plasminogen activator (tPA), a safe and effective therapy with nearly 2 decades of evidence to support its use.¹⁰ The treating physician should carefully review the risks and benefits of this therapy.

To receive tPA, the patient must have all of the following:

• Clinical diagnosis of ischemic stroke with measurable neurologic deficit
• Onset of symptoms within the past 3 hours
• Age 18 or older.

The patient must not have any of the following:

• Significant stroke within the past 3 months
• Severe traumatic head injury within the past 3 months
• History of significant intracerebral hemorrhage
• Previously ruptured arteriovenous malformation or intracranial aneurysm
• Central nervous system neoplasm
• Arterial puncture at a noncompressible site within the past 7 days
• Evidence of hemorrhage on CT of the head
• Evidence of ischemia in greater than 33% of the cerebral hemisphere on head CT
• History and symptoms strongly suggesting subarachnoid hemorrhage
• Persistent hypertension (systolic pressure ≥ 185 mm Hg or diastolic pressure ≥ 110 mm Hg)
• Evidence of acute significant bleeding (external or internal)
• Hypoglycemia—ie, serum glucose less than 50 mg/dL (< 2.8 mmol/L)
• Thrombocytopenia (platelet count < 100 × 10⁹/L)
• Significant coagulopathy (international normalized ratio > 1.7, prothrombin time > 15 seconds, or abnormally elevated activated partial thromboplastin time)
• Current use of a factor Xa inhibitor or direct thrombin inhibitor.

Relative contraindications:

• Minor or rapidly resolving symptoms
• Major surgery or trauma within the past 14 days
• Gastrointestinal or urinary tract bleeding within the past 21 days
• Myocardial infarction in the past 3 months
• Unruptured intracranial aneurysm
• Seizure occurring at stroke onset
• Pregnancy.

If these criteria are satisfied, tPA should be given at a dose of 0.9 mg/kg intravenously over 60 minutes. Ten percent  of the dose should be given as an initial bolus, followed by a constant infusion of the remaining 90% over 1 hour.

If tPA is given, the blood pressure must be kept lower than 185/110 mm Hg to minimize the risk of symptomatic intracerebral hemorrhage.

A subset of patients may benefit from receiving intravenous tPA between 3 and 4.5 hours after the onset of stroke symptoms. These include patients who are no more than 80 years old, who have not recently used oral anticoagulants, who do not have severe neurologic injury (ie, do not have NIH Stroke Scale scores > 25), and who do not have diabetes mellitus or a history of ischemic stroke.¹¹ Although many hospitals have such a protocol for tPA up to 4.5 hours after the onset of stroke symptoms, this time window is not currently approved by the US Food and Drug Administration.

Intra-arterial therapy. Based on recent trials, some patients may benefit further from intra-arterial thrombolysis or mechanical thrombectomy, both delivered during catheter-based cerebral angiography, independent of intravenous tPA administration.^12,13 These patients should be evaluated on a case-by-case basis by a neurologist and neurointerventional team. Time windows for these treatments generally extend to 6 hours from stroke onset and perhaps even longer in some situations (eg, basilar artery occlusion).

An antiplatelet agent should be started quickly in all stroke patients who do not receive tPA. Patients who receive tPA can begin receiving an antiplatelet agent 24 hours afterward.

Unfractionated heparin. There is no evidence to support the use of unfractionated heparin in most cases of acute ischemic stroke.¹⁰

Glucose control (in the range of 140–180 mg/dL) and fever control remain essential elements of post-acute stroke care to provide additional protection to the damaged brain.

For ischemic stroke due to atrial fibrillation

In ischemic stroke due to atrial fibrillation, early anticoagulation should be considered, based on the CHA₂DS₂-VASC risk of ischemic stroke vs the HAS-BLED risk of hemorrhage (calculators available at www.mdcalc.com).

In general, anticoagulation may be withheld during the first 72 hours while further stroke workup and evaluation of extent of injury are carried out, as there is an increased risk of hemorrhagic transformation of the ischemic stroke. Often, anticoagulation is resumed at a full dose between 72 hours and 2 weeks of the ischemic stroke.

ACUTE HEMORRHAGIC STROKE: BLOOD PRESSURE, COAGULATION

Approximately 15% of strokes are caused by intracerebral hemorrhage, which can be detected with noncontrast head CT with a sensitivity of 98.6% within 6 hours of the onset of bleeding.¹⁴ A common underlying cause of intracerebral hemorrhage is chronic poorly controlled hypertension, causing rupture of damaged (or “lipohyalinized”) vessels with resultant blood extravasation into the brain parenchyma. Other causes are less common (Table 2).

Treatment of acute hemorrhagic stroke

Acute treatment of intracerebral hemorrhage includes blood pressure control, reversal of underlying coagulopathy or anticoagulation, and sometimes intracranial pressure control. There is little role for surgery in most cases, based on findings of randomized trials.¹⁵

Blood pressure control. Many studies have investigated optimal blood pressure goals in acute intracerebral hemorrhage. Recent data suggest that early aggressive therapy, targeting a systolic blood pressure goal less than 140 mm Hg within the first hour, is safe and can lead to better functional outcomes than a more conservative blood-pressure-lowering target.¹⁶ Rapid-onset, short-acting antihypertensive agents in intravenous form, such as nicardipine and labetalol, are frequently used. Of note, this treatment strategy for hemorrhagic stroke is in direct contrast to the treatment of ischemic stroke, in which permissive hypertension (blood pressure goal < 220/110 mm Hg) is often pursued.

Reversal of any coagulation abnormalities should be done quickly in intracranial hemorrhage. Warfarin use has been shown to be a strong independent predictor of intracranial hemorrhage expansion, which increases the risk of death.^17,18

Increasingly, agents other than vitamin K or fresh-frozen plasma are being used to rapidly reverse anticoagulation, including prothrombin complex concentrate (available in three- and four-factor preparations) and recombinant factor VIIa. While four-factor prothrombin complex concentrate and recombinant factor VIIa have been shown to be more efficacious than fresh-frozen plasma, there are limited data directly comparing these newer reversal agents against each other.¹⁹ The use of these medications is limited by availability and practitioner familiarity.^20–22

Reversing anticoagulation due to target-specific oral anticoagulants. The acute management of intracranial hemorrhage in patients taking the new target-specific oral anticoagulants (eg, dabigatran, apixaban, rivaroxaban, edoxaban) remains challenging. Laboratory tests such as factor Xa levels are not readily available in many institutions and do not provide results in a timely fashion, and in the interim, acute hemorrhage and clinical deterioration may occur. Management strategies involve giving fresh-frozen plasma, prothrombin complex concentrate, and consideration of hemodialysis.²³ Dabigatran reversal with idarucizumab has recently been shown to have efficacy.²⁴

Vigilance for elevated intracranial pressure. Intracranial hemorrhage can occasionally cause elevated intracranial pressure, which should be treated rapidly. Any acute decline in mental status in a patient with intracranial hemorrhage requires emergency imaging to evaluate for expansion of hemorrhage.

SUBARACHNOID HEMORRHAGE

The sudden onset of a “thunderclap” headache (often described by patients as “the worst headache of my life”) suggests subarachnoid hemorrhage.

In contrast to intracranial hemorrhage, in subarachnoid hemorrhage blood collects mainly in the cerebral spinal fluid-containing spaces surrounding the brain, leading to a higher incidence of hydrocephalus from impaired drainage of cerebrospinal fluid. Nontraumatic subarachnoid hemorrhage is most often caused by rupture of an intracranial aneurysm, which can be a devastating event, with death rates approaching 50%.²⁵

Diagnosis of subarachnoid hemorrhage

Noncontrast CT of the head is the main modality for diagnosing subarachnoid hemorrhage. Blood within the subarachnoid space is demonstrable in 92% of cases if CT is performed within the first 24 hours of hemorrhage, with an initial sensitivity of about 95% within the first 6 hours of onset.^14,26,27 The longer CT is delayed, the lower the sensitivity.

Some studies suggest that a protocol of CT followed by CT angiography can safely exclude aneurysmal subarachnoid hemorrhage and obviate the need for lumbar puncture. However, further research is required to validate this approach.²⁸

Lumbar puncture. If clinical suspicion of subarachnoid hemorrhage remains strong even though initial CT is negative, lumbar puncture must be performed for cerebrospinal fluid analysis.²⁹ Xanthochromia (a yellowish pigmentation of the cerebrospinal fluid due to the degeneration of blood products that occurs within 8 to 12 hours of bleeding) should raise the alarm for subarachnoid hemorrhage; this sign may be present up to 4 weeks after the bleeding event.³⁰

If lumbar puncture is contraindicated, then aneurysmal subarachnoid hemorrhage has not been ruled out, and further neurologic consultation should be pursued.

Management of subarachnoid hemorrhage

Early management of blood pressure for a ruptured intracranial aneurysm follows strategies similar to those for intracranial hemorrhage. Further investigation is rapidly directed toward an underlying vascular malformation, with intracranial vessel imaging such as CT angiography, magnetic resonance angiography, or the gold standard test—catheter-based cerebral angiography.

Aneurysms are treated (or “secured”) either by surgical clipping or by endovascular coiling. Endovascular coiling is preferable in cases in which both can be safely attempted.³¹ If the facility lacks the resources to do these procedures, the patient should be referred to a nearby tertiary care center.

INTRACRANIAL HYPERTENSION: DANGER OF BRAIN HERNIATION

A number of conditions can cause an acute intracranial pressure elevation. The danger of brain herniation requires that therapies be implemented rapidly to prevent catastrophic neurologic injury. In many situations, nonneurologists are the first responders and therefore should be familiar with basic intracranial pressure management.

Initial symptoms of acute rise in intracranial pressure

As intracranial pressure rises, pressure is typically equally distributed throughout the cranial vault, leading to dysfunction of the ascending reticular activating system, which clinically manifests as the inability to stay alert despite varying degrees of noxious stimulation. Progressive cranial neuropathies (often starting with pupillary abnormalities) and coma are often seen in this setting as the upper brainstem begins to be compressed.

Initial assessment and treatment of elevated intracranial pressure

Noncontrast CT of the head is often obtained immediately when acutely elevated intracranial pressure is suspected. If clinical examination and radiographic findings are consistent with intracranial hypertension, prompt measures can be started at the bedside.

Elevate the head of the bed to 30 degrees to promote venous drainage and reduce intracranial pressure. (In contrast, most other hemodynamically unstable patients are placed flat or in the Trendelenburg position.)

Intubation should be done quickly in cases of airway compromise, and hyperventilation should be started with a goal Paco₂ of 30 to 35 mm Hg. This hypocarbic strategy promotes cerebral vasoconstriction and a transient decrease in intracranial pressure.

Hyperosmolar therapy allows for transient intracranial volume decompression and is the mainstay of emergency medical treatment of intracranial hypertension. Mannitol is a hyper­osmolar polysaccharide that promotes osmotic diuresis and removes excessive cerebral water. In the acute setting, it can be given as an intravenous bolus of 1 to 2 g/kg through a peripheral intravenous line, followed by a bolus every 4 to 6 hours. Hypotension can occur after diuresis, and renal function should be closely monitored since frequent mannitol use can promote acute tubular necrosis. In patients who are anuric, the medication is typically not used.

Hypertonic saline (typically 3% sodium chloride, though different concentrations are available) is an alternative that helps draw interstitial fluid into the intravascular space, decreasing cerebral edema and maintaining hemodynamic stability. Relative contraindications include congestive heart failure or renal failure leading to pulmonary edema from volume overload. Hypertonic saline can be given as a bolus or a constant infusion. Some institutions have rapid access to 23.4% saline, which can be given as a 30-mL bolus but typically requires a central venous catheter for rapid infusion.

Comatose patients with radiographic findings of hydrocephalus, epidural or subdural hematoma, or mass effect with midline shift warrant prompt neurosurgical consultation for further surgical measures of intracranial pressure control and monitoring.

The ‘blown’ pupil

The physician should be concerned about elevated intracranial pressure if a patient has mydriasis, ie, an abnormally dilated (“blown”) pupil, which is a worrisome sign in the setting of true intracranial hypertension. However, many different processes can cause mydriasis and should be kept in mind when evaluating this finding (Table 3).³² If radiographic findings do not suggest elevated intracranial pressure, further workup into these other processes should be pursued.

STATUS EPILEPTICUS: SEIZURE CONTROL IS IMPORTANT

A continuous unremitting seizure lasting longer than 5 minutes or recurrent seizure activity in a patient who does not regain consciousness between seizures should be treated as status epilepticus. All seizure types carry the risk of progressing to status epilepticus, and responsiveness to antiepileptic drug therapy is inversely related to the duration of seizures. It is imperative that seizure activity be treated early and aggressively to prevent recalcitrant seizure activity, neuronal damage, and progression to status epilepticus.³³

Once the ABCs of emergency stabilization have been performed (ie, airway, breathing, circulation), antiepileptic drug therapy should start immediately using established algorithms (Figure 1).^34–36 During the course of treatment, the reliability of the neurologic examination may be limited due to medication effects or continued status epilepticus, making continuous video electroencephalographic monitoring often necessary to guide further therapy in patients who are not rapidly recovering.^34–38

Once status epilepticus has resolved, further investigation into the underlying cause should be pursued quickly, especially in patients without a previous diagnosis of epilepsy. Head CT with contrast or magnetic resonance imaging can be used to look for any structural abnormality that may explain seizures. Basic laboratory tests including toxicology screening can identify a common trigger such as hypoglycemia or stimulant use. Fever or other possible signs of meningitis should be investigated further with cerebrospinal fluid analysis.

SPINAL CORD INJURY

Acute spinal cord injury can lead to substantial long-term neurologic impairment and should be suspected in any patient presenting with focal motor loss, sensory loss, or both with sparing of the cranial nerves and mental status. Causes of injury include compression (traumatic or nontraumatic) and inflammatory and noninflammatory myelopathies.

The location of the injury can be inferred by analyzing the symptoms, which can point to the cord level and indicate whether the anterior or posterior of the cord is involved. Anterior cord injury tends to affect the descending corticospinal and pyramidal tracts, resulting in motor deficits and weakness. Posterior cord injury involves the dorsal columns, leading to deficits of vibration sensation and proprioception. High cervical cord injuries tend to involve varying degrees of quadriparesis, sensory loss, and sometimes respiratory compromise. A clinical history of bilateral lower-extremity weakness, a “band-like” sensory complaint around the lower chest or abdomen, or both, can suggest thoracic cord involvement. Symptoms isolated to one or both lower extremities along with lower back pain and bowel or bladder involvement may point to injury of the lumbosacral cord.

Basic management of spinal cord injury includes decompression of the bladder and initial protection against further injury with a stabilizing collar or brace.

Magnetic resonance imaging with and without contrast is the ideal study to evaluate injuries to the spinal cord itself. While CT is helpful in identifying bony disease of the spinal column (eg, evaluating traumatic fractures), it is not helpful in viewing intrinsic cord pathology.

Traumatic myelopathy

Traumatic spinal cord injury is usually suggested by the clinical history and confirmed with CT. In this setting, early consultation with a neurosurgeon is required to prevent permanent cord injury.

Guidelines suggest maintaining a mean arterial pressure greater than 85 to 90 mm Hg for the first 7 days after traumatic spinal cord injury, a particular problem in the setting of hemodynamic instability, which can accompany lesions above the midthoracic level.^39,40

Patients with vertebral body misalignment should be placed in an appropriate stabilizing collar or brace until a medically trained professional deems it appropriate to discontinue the device, or until surgical stabilization is performed.

Methylprednisone is a controversial intervention for acute spinal cord trauma, lacking clear benefit in meta-analyses.⁴¹

Nontraumatic compressive myelopathy

Patients with nontraumatic compressive myelopathy tend to present with varying degrees of back pain and worsening sensorimotor function. The differential diagnosis includes epidural abscesses, hematoma, metastatic neoplasm, and osteophyte compression (Table 4). The clinical history helps to guide therapy and should involve assessment for previous spinal column injury, immunocompromised state, travel history (which provides information on risks of exposure to a variety of diseases, including infections), and constitutional symptoms such as fever and weight loss.

Epidural abscess can have devastating results if missed. Red flags such as recent illness, intravenous drug use, focal back pain, fever, worsening numbness or weakness, and bowel or bladder incontinence should raise suspicion of this disorder. Emergency magnetic resonance imaging is required to diagnose this condition, and treatment involves urgent administration of antibiotics and consideration of surgical drainage.

Noncompressive myelopathies

There are numerous causes of noncompressive spinal cord injury (Table 4), and the etiology may be inflammatory (eg, “myelitis”) or noninflammatory. The diagnostic workup may require both magnetic resonance imaging and cerebrospinal fluid analysis. Acute disease-targeted therapy is rarely indicated and can be deferred until a full diagnostic workup has been completed.

NEUROMUSCULAR DISEASE: IS VENTILATION NEEDED?

Diseases involving the motor components of the peripheral nervous system (Table 5) share the common risk of causing ventilatory failure due to weakness of the diaphragm, intercostal muscles, and upper-airway muscles. Clinicians need to be aware of this risk and view these disorders as neurologic emergencies.

Determining when these patients require mechanical intubation is a challenge. Serial measurements of maximum inspiratory force and vital capacity are important and can be accomplished quickly at the bedside by a respiratory therapist. A maximum inspiratory force less than –30 cm H₂O or a vital capacity less than 20 mL/kg, or both, are worrisome markers that raise concern for impending ventilatory failure. Serial measurements can detect changes in these values that might indicate the need for elective intubation. In any patient presenting with weakness of the limbs, these measurements are an important step in the initial evaluation.

Myasthenic crisis

Myasthenia gravis is caused by autoantibodies directed against postsynaptic acetylcholine receptors. Patients demonstrate muscle weakness, usually in a proximal pattern, with fatigue, respiratory distress, nasal speech, ophthalmoparesis, and dysphagia. Exacerbations can occur as a response to recent infection, surgery, or medications such as neuromuscular blocking agents or aminoglycosides.

Myasthenic crisis, while uncommon, is a life-threatening emergency characterized by bulbar or respiratory failure secondary to muscle weakness. It can occur in patients already diagnosed with myasthenia gravis or may be the initial manifestation of the disease.^42–49 Intubation and mechanical ventilation are frequently required. Postoperative myasthenic patients in whom extubation has been delayed more than 24 hours should be considered in crisis.⁴⁵

The diagnosis of myasthenia gravis can be made by serum autoantibody testing, electromyography, and nerve conduction studies (with repetitive stimulation) or administration of edrophonium in patients with obvious ptosis.

The mainstay of therapy for myasthenic crisis is either intravenous immunoglobulin at a dose of 2 g/kg over 2 to 5 days or plasmapheresis (5–7 exchanges over 7–14 days). Corticosteroids are not recommended in myasthenic crisis in patients who are not intubated, as they can potentiate an initial worsening of crisis. Once the patient begins to show clinical improvement, outpatient pyridostigmine and immunosuppressive medications can be resumed at a low dose and titrated as tolerated.

Acute inflammatory demyelinating polyneuropathy (Guillain-Barré syndrome)

Acute inflammatory demyelinating polyneuropathy is an autoimmune disorder involving autoantibodies against axons or myelin in the peripheral nervous system.

This disease should be suspected in a patient who is developing worsening muscle weakness (usually with areflexia) over the course of days to weeks. Occasionally, a recent diarrheal or other systemic infectious trigger can be identified. Blood pressure instability and cardiac arrhythmia can also be seen due to autonomic nerve involvement. Although classically described as an “ascending paralysis,” other variants of this disease have distinct clinical presentations (eg, the descending paralysis, ataxia, areflexia, ophthalmoparesis of the Miller Fisher syndrome).

Acute inflammatory demyelinating polyneuropathy is diagnosed by electromyography and nerve conduction studies. A cerebrospinal fluid profile demonstrating elevated protein and few white blood cells is typical.

Treatment, as in myasthenic crisis, involves intravenous immunoglobulin or plasmapheresis. Corticosteroids are ineffective. Anticipation of ventilatory failure and expectant intubation is essential, given the progressive nature of the disorder.⁵⁰

Neurologic emergencies such as acute stroke, status epilepticus, subarachnoid hemorrhage, neuromuscular weakness, and spinal cord injury affect millions of Americans yearly.^1,2 These conditions can be difficult to diagnose, and delays in recognition and treatment can have devastating results. Consequently, it is important for nonneurologists to be able to quickly recognize these conditions and initiate timely management, often while awaiting neurologic consultation.

Here, we review how to recognize and treat these common, serious conditions.

ACUTE ISCHEMIC STROKE: TIME IS OF THE ESSENCE

Stroke is the fourth leading cause of death in the United States and is one of the most common causes of disability worldwide.^3–5 About 85% of strokes are ischemic, resulting from diminished vascular supply to the brain. Symptoms such as facial droop, unilateral weakness or numbness, aphasia, gaze deviation, and unsteadiness of gait may be seen. Time is of the essence, as all currently available interventions are safe and effective only within defined time windows.

Diagnosis and assessment

When acute ischemic stroke is suspected, the clinical history, time of onset, and basic neurologic examination should be obtained quickly.

The National Institutes of Health (NIH) stroke scale is an objective marker for assessing stroke severity as well as evolution of disease and should be obtained in all stroke patients. Scores range from 0 (best) to 42 (worst) (www.ninds.nih.gov/doctors/NIH_Stroke_Scale.pdf).

Time of onset of symptoms is essential to determine, since it guides eligibility for acute therapies. Clinicians should ascertain the last time the patient was seen to be neurologically well in order to estimate this time window as closely as possible.

Laboratory tests should include a fingerstick blood glucose measurement, coagulation studies, complete blood cell count, and basic metabolic profile.

Computed tomography (CT) of the head without contrast should be obtained immediately to exclude acute hemorrhage and any alternative diagnoses that could explain the patient’s symptoms. Acute brain ischemia is often not apparent on CT during the first few hours of injury. Therefore, a patient presenting with new focal neurologic deficits and an unremarkable result on CT of the head should be treated as having had an acute ischemic stroke, and interventional therapies should be considered.

Stroke mimics should be considered and treated, as appropriate (Table 1).

Acute management of ischemic stroke

Acute treatment should not be delayed by obtaining chest radiography, inserting a Foley catheter, or obtaining an electrocardiogram. The longer the time that elapses before treatment, the worse the functional outcome, underscoring the need for rapid decision-making.^6–8

Lowering the head of the bed may provide benefit by promoting blood flow to ischemic brain tissue.⁹ However, this should not be done in patients with significantly elevated intracerebral pressure and concern for herniation.

Permissive hypertension (antihypertensive treatment only for blood pressure greater than 220/110 mm Hg) should be allowed per national guidelines to provide adequate perfusion to brain areas at risk of injury.¹⁰

Tissue plasminogen activator. Patients with ischemic stroke who present within 3 hours of symptom onset should be considered for intravenous administration of tissue plasminogen activator (tPA), a safe and effective therapy with nearly 2 decades of evidence to support its use.¹⁰ The treating physician should carefully review the risks and benefits of this therapy.

To receive tPA, the patient must have all of the following:

• Clinical diagnosis of ischemic stroke with measurable neurologic deficit
• Onset of symptoms within the past 3 hours
• Age 18 or older.

The patient must not have any of the following:

• Significant stroke within the past 3 months
• Severe traumatic head injury within the past 3 months
• History of significant intracerebral hemorrhage
• Previously ruptured arteriovenous malformation or intracranial aneurysm
• Central nervous system neoplasm
• Arterial puncture at a noncompressible site within the past 7 days
• Evidence of hemorrhage on CT of the head
• Evidence of ischemia in greater than 33% of the cerebral hemisphere on head CT
• History and symptoms strongly suggesting subarachnoid hemorrhage
• Persistent hypertension (systolic pressure ≥ 185 mm Hg or diastolic pressure ≥ 110 mm Hg)
• Evidence of acute significant bleeding (external or internal)
• Hypoglycemia—ie, serum glucose less than 50 mg/dL (< 2.8 mmol/L)
• Thrombocytopenia (platelet count < 100 × 10⁹/L)
• Significant coagulopathy (international normalized ratio > 1.7, prothrombin time > 15 seconds, or abnormally elevated activated partial thromboplastin time)
• Current use of a factor Xa inhibitor or direct thrombin inhibitor.

Relative contraindications:

• Minor or rapidly resolving symptoms
• Major surgery or trauma within the past 14 days
• Gastrointestinal or urinary tract bleeding within the past 21 days
• Myocardial infarction in the past 3 months
• Unruptured intracranial aneurysm
• Seizure occurring at stroke onset
• Pregnancy.

If these criteria are satisfied, tPA should be given at a dose of 0.9 mg/kg intravenously over 60 minutes. Ten percent  of the dose should be given as an initial bolus, followed by a constant infusion of the remaining 90% over 1 hour.

If tPA is given, the blood pressure must be kept lower than 185/110 mm Hg to minimize the risk of symptomatic intracerebral hemorrhage.

A subset of patients may benefit from receiving intravenous tPA between 3 and 4.5 hours after the onset of stroke symptoms. These include patients who are no more than 80 years old, who have not recently used oral anticoagulants, who do not have severe neurologic injury (ie, do not have NIH Stroke Scale scores > 25), and who do not have diabetes mellitus or a history of ischemic stroke.¹¹ Although many hospitals have such a protocol for tPA up to 4.5 hours after the onset of stroke symptoms, this time window is not currently approved by the US Food and Drug Administration.

Intra-arterial therapy. Based on recent trials, some patients may benefit further from intra-arterial thrombolysis or mechanical thrombectomy, both delivered during catheter-based cerebral angiography, independent of intravenous tPA administration.^12,13 These patients should be evaluated on a case-by-case basis by a neurologist and neurointerventional team. Time windows for these treatments generally extend to 6 hours from stroke onset and perhaps even longer in some situations (eg, basilar artery occlusion).

An antiplatelet agent should be started quickly in all stroke patients who do not receive tPA. Patients who receive tPA can begin receiving an antiplatelet agent 24 hours afterward.

Unfractionated heparin. There is no evidence to support the use of unfractionated heparin in most cases of acute ischemic stroke.¹⁰

Glucose control (in the range of 140–180 mg/dL) and fever control remain essential elements of post-acute stroke care to provide additional protection to the damaged brain.

For ischemic stroke due to atrial fibrillation

In ischemic stroke due to atrial fibrillation, early anticoagulation should be considered, based on the CHA₂DS₂-VASC risk of ischemic stroke vs the HAS-BLED risk of hemorrhage (calculators available at www.mdcalc.com).

In general, anticoagulation may be withheld during the first 72 hours while further stroke workup and evaluation of extent of injury are carried out, as there is an increased risk of hemorrhagic transformation of the ischemic stroke. Often, anticoagulation is resumed at a full dose between 72 hours and 2 weeks of the ischemic stroke.

ACUTE HEMORRHAGIC STROKE: BLOOD PRESSURE, COAGULATION

Approximately 15% of strokes are caused by intracerebral hemorrhage, which can be detected with noncontrast head CT with a sensitivity of 98.6% within 6 hours of the onset of bleeding.¹⁴ A common underlying cause of intracerebral hemorrhage is chronic poorly controlled hypertension, causing rupture of damaged (or “lipohyalinized”) vessels with resultant blood extravasation into the brain parenchyma. Other causes are less common (Table 2).

Treatment of acute hemorrhagic stroke

Acute treatment of intracerebral hemorrhage includes blood pressure control, reversal of underlying coagulopathy or anticoagulation, and sometimes intracranial pressure control. There is little role for surgery in most cases, based on findings of randomized trials.¹⁵

Blood pressure control. Many studies have investigated optimal blood pressure goals in acute intracerebral hemorrhage. Recent data suggest that early aggressive therapy, targeting a systolic blood pressure goal less than 140 mm Hg within the first hour, is safe and can lead to better functional outcomes than a more conservative blood-pressure-lowering target.¹⁶ Rapid-onset, short-acting antihypertensive agents in intravenous form, such as nicardipine and labetalol, are frequently used. Of note, this treatment strategy for hemorrhagic stroke is in direct contrast to the treatment of ischemic stroke, in which permissive hypertension (blood pressure goal < 220/110 mm Hg) is often pursued.

Reversal of any coagulation abnormalities should be done quickly in intracranial hemorrhage. Warfarin use has been shown to be a strong independent predictor of intracranial hemorrhage expansion, which increases the risk of death.^17,18

Increasingly, agents other than vitamin K or fresh-frozen plasma are being used to rapidly reverse anticoagulation, including prothrombin complex concentrate (available in three- and four-factor preparations) and recombinant factor VIIa. While four-factor prothrombin complex concentrate and recombinant factor VIIa have been shown to be more efficacious than fresh-frozen plasma, there are limited data directly comparing these newer reversal agents against each other.¹⁹ The use of these medications is limited by availability and practitioner familiarity.^20–22

Reversing anticoagulation due to target-specific oral anticoagulants. The acute management of intracranial hemorrhage in patients taking the new target-specific oral anticoagulants (eg, dabigatran, apixaban, rivaroxaban, edoxaban) remains challenging. Laboratory tests such as factor Xa levels are not readily available in many institutions and do not provide results in a timely fashion, and in the interim, acute hemorrhage and clinical deterioration may occur. Management strategies involve giving fresh-frozen plasma, prothrombin complex concentrate, and consideration of hemodialysis.²³ Dabigatran reversal with idarucizumab has recently been shown to have efficacy.²⁴

Vigilance for elevated intracranial pressure. Intracranial hemorrhage can occasionally cause elevated intracranial pressure, which should be treated rapidly. Any acute decline in mental status in a patient with intracranial hemorrhage requires emergency imaging to evaluate for expansion of hemorrhage.

SUBARACHNOID HEMORRHAGE

The sudden onset of a “thunderclap” headache (often described by patients as “the worst headache of my life”) suggests subarachnoid hemorrhage.

In contrast to intracranial hemorrhage, in subarachnoid hemorrhage blood collects mainly in the cerebral spinal fluid-containing spaces surrounding the brain, leading to a higher incidence of hydrocephalus from impaired drainage of cerebrospinal fluid. Nontraumatic subarachnoid hemorrhage is most often caused by rupture of an intracranial aneurysm, which can be a devastating event, with death rates approaching 50%.²⁵

Diagnosis of subarachnoid hemorrhage

Noncontrast CT of the head is the main modality for diagnosing subarachnoid hemorrhage. Blood within the subarachnoid space is demonstrable in 92% of cases if CT is performed within the first 24 hours of hemorrhage, with an initial sensitivity of about 95% within the first 6 hours of onset.^14,26,27 The longer CT is delayed, the lower the sensitivity.

Some studies suggest that a protocol of CT followed by CT angiography can safely exclude aneurysmal subarachnoid hemorrhage and obviate the need for lumbar puncture. However, further research is required to validate this approach.²⁸

Lumbar puncture. If clinical suspicion of subarachnoid hemorrhage remains strong even though initial CT is negative, lumbar puncture must be performed for cerebrospinal fluid analysis.²⁹ Xanthochromia (a yellowish pigmentation of the cerebrospinal fluid due to the degeneration of blood products that occurs within 8 to 12 hours of bleeding) should raise the alarm for subarachnoid hemorrhage; this sign may be present up to 4 weeks after the bleeding event.³⁰

If lumbar puncture is contraindicated, then aneurysmal subarachnoid hemorrhage has not been ruled out, and further neurologic consultation should be pursued.

Management of subarachnoid hemorrhage

Early management of blood pressure for a ruptured intracranial aneurysm follows strategies similar to those for intracranial hemorrhage. Further investigation is rapidly directed toward an underlying vascular malformation, with intracranial vessel imaging such as CT angiography, magnetic resonance angiography, or the gold standard test—catheter-based cerebral angiography.

Aneurysms are treated (or “secured”) either by surgical clipping or by endovascular coiling. Endovascular coiling is preferable in cases in which both can be safely attempted.³¹ If the facility lacks the resources to do these procedures, the patient should be referred to a nearby tertiary care center.

INTRACRANIAL HYPERTENSION: DANGER OF BRAIN HERNIATION

A number of conditions can cause an acute intracranial pressure elevation. The danger of brain herniation requires that therapies be implemented rapidly to prevent catastrophic neurologic injury. In many situations, nonneurologists are the first responders and therefore should be familiar with basic intracranial pressure management.

Initial symptoms of acute rise in intracranial pressure

As intracranial pressure rises, pressure is typically equally distributed throughout the cranial vault, leading to dysfunction of the ascending reticular activating system, which clinically manifests as the inability to stay alert despite varying degrees of noxious stimulation. Progressive cranial neuropathies (often starting with pupillary abnormalities) and coma are often seen in this setting as the upper brainstem begins to be compressed.

Initial assessment and treatment of elevated intracranial pressure

Noncontrast CT of the head is often obtained immediately when acutely elevated intracranial pressure is suspected. If clinical examination and radiographic findings are consistent with intracranial hypertension, prompt measures can be started at the bedside.

Elevate the head of the bed to 30 degrees to promote venous drainage and reduce intracranial pressure. (In contrast, most other hemodynamically unstable patients are placed flat or in the Trendelenburg position.)

Intubation should be done quickly in cases of airway compromise, and hyperventilation should be started with a goal Paco₂ of 30 to 35 mm Hg. This hypocarbic strategy promotes cerebral vasoconstriction and a transient decrease in intracranial pressure.

Hyperosmolar therapy allows for transient intracranial volume decompression and is the mainstay of emergency medical treatment of intracranial hypertension. Mannitol is a hyper­osmolar polysaccharide that promotes osmotic diuresis and removes excessive cerebral water. In the acute setting, it can be given as an intravenous bolus of 1 to 2 g/kg through a peripheral intravenous line, followed by a bolus every 4 to 6 hours. Hypotension can occur after diuresis, and renal function should be closely monitored since frequent mannitol use can promote acute tubular necrosis. In patients who are anuric, the medication is typically not used.

Hypertonic saline (typically 3% sodium chloride, though different concentrations are available) is an alternative that helps draw interstitial fluid into the intravascular space, decreasing cerebral edema and maintaining hemodynamic stability. Relative contraindications include congestive heart failure or renal failure leading to pulmonary edema from volume overload. Hypertonic saline can be given as a bolus or a constant infusion. Some institutions have rapid access to 23.4% saline, which can be given as a 30-mL bolus but typically requires a central venous catheter for rapid infusion.

Comatose patients with radiographic findings of hydrocephalus, epidural or subdural hematoma, or mass effect with midline shift warrant prompt neurosurgical consultation for further surgical measures of intracranial pressure control and monitoring.

The ‘blown’ pupil

The physician should be concerned about elevated intracranial pressure if a patient has mydriasis, ie, an abnormally dilated (“blown”) pupil, which is a worrisome sign in the setting of true intracranial hypertension. However, many different processes can cause mydriasis and should be kept in mind when evaluating this finding (Table 3).³² If radiographic findings do not suggest elevated intracranial pressure, further workup into these other processes should be pursued.

STATUS EPILEPTICUS: SEIZURE CONTROL IS IMPORTANT

A continuous unremitting seizure lasting longer than 5 minutes or recurrent seizure activity in a patient who does not regain consciousness between seizures should be treated as status epilepticus. All seizure types carry the risk of progressing to status epilepticus, and responsiveness to antiepileptic drug therapy is inversely related to the duration of seizures. It is imperative that seizure activity be treated early and aggressively to prevent recalcitrant seizure activity, neuronal damage, and progression to status epilepticus.³³

Once the ABCs of emergency stabilization have been performed (ie, airway, breathing, circulation), antiepileptic drug therapy should start immediately using established algorithms (Figure 1).^34–36 During the course of treatment, the reliability of the neurologic examination may be limited due to medication effects or continued status epilepticus, making continuous video electroencephalographic monitoring often necessary to guide further therapy in patients who are not rapidly recovering.^34–38

Once status epilepticus has resolved, further investigation into the underlying cause should be pursued quickly, especially in patients without a previous diagnosis of epilepsy. Head CT with contrast or magnetic resonance imaging can be used to look for any structural abnormality that may explain seizures. Basic laboratory tests including toxicology screening can identify a common trigger such as hypoglycemia or stimulant use. Fever or other possible signs of meningitis should be investigated further with cerebrospinal fluid analysis.

SPINAL CORD INJURY

Acute spinal cord injury can lead to substantial long-term neurologic impairment and should be suspected in any patient presenting with focal motor loss, sensory loss, or both with sparing of the cranial nerves and mental status. Causes of injury include compression (traumatic or nontraumatic) and inflammatory and noninflammatory myelopathies.

The location of the injury can be inferred by analyzing the symptoms, which can point to the cord level and indicate whether the anterior or posterior of the cord is involved. Anterior cord injury tends to affect the descending corticospinal and pyramidal tracts, resulting in motor deficits and weakness. Posterior cord injury involves the dorsal columns, leading to deficits of vibration sensation and proprioception. High cervical cord injuries tend to involve varying degrees of quadriparesis, sensory loss, and sometimes respiratory compromise. A clinical history of bilateral lower-extremity weakness, a “band-like” sensory complaint around the lower chest or abdomen, or both, can suggest thoracic cord involvement. Symptoms isolated to one or both lower extremities along with lower back pain and bowel or bladder involvement may point to injury of the lumbosacral cord.

Basic management of spinal cord injury includes decompression of the bladder and initial protection against further injury with a stabilizing collar or brace.

Magnetic resonance imaging with and without contrast is the ideal study to evaluate injuries to the spinal cord itself. While CT is helpful in identifying bony disease of the spinal column (eg, evaluating traumatic fractures), it is not helpful in viewing intrinsic cord pathology.

Traumatic myelopathy

Traumatic spinal cord injury is usually suggested by the clinical history and confirmed with CT. In this setting, early consultation with a neurosurgeon is required to prevent permanent cord injury.

Guidelines suggest maintaining a mean arterial pressure greater than 85 to 90 mm Hg for the first 7 days after traumatic spinal cord injury, a particular problem in the setting of hemodynamic instability, which can accompany lesions above the midthoracic level.^39,40

Patients with vertebral body misalignment should be placed in an appropriate stabilizing collar or brace until a medically trained professional deems it appropriate to discontinue the device, or until surgical stabilization is performed.

Methylprednisone is a controversial intervention for acute spinal cord trauma, lacking clear benefit in meta-analyses.⁴¹

Nontraumatic compressive myelopathy

Patients with nontraumatic compressive myelopathy tend to present with varying degrees of back pain and worsening sensorimotor function. The differential diagnosis includes epidural abscesses, hematoma, metastatic neoplasm, and osteophyte compression (Table 4). The clinical history helps to guide therapy and should involve assessment for previous spinal column injury, immunocompromised state, travel history (which provides information on risks of exposure to a variety of diseases, including infections), and constitutional symptoms such as fever and weight loss.

Epidural abscess can have devastating results if missed. Red flags such as recent illness, intravenous drug use, focal back pain, fever, worsening numbness or weakness, and bowel or bladder incontinence should raise suspicion of this disorder. Emergency magnetic resonance imaging is required to diagnose this condition, and treatment involves urgent administration of antibiotics and consideration of surgical drainage.

Noncompressive myelopathies

There are numerous causes of noncompressive spinal cord injury (Table 4), and the etiology may be inflammatory (eg, “myelitis”) or noninflammatory. The diagnostic workup may require both magnetic resonance imaging and cerebrospinal fluid analysis. Acute disease-targeted therapy is rarely indicated and can be deferred until a full diagnostic workup has been completed.

NEUROMUSCULAR DISEASE: IS VENTILATION NEEDED?

Diseases involving the motor components of the peripheral nervous system (Table 5) share the common risk of causing ventilatory failure due to weakness of the diaphragm, intercostal muscles, and upper-airway muscles. Clinicians need to be aware of this risk and view these disorders as neurologic emergencies.

Determining when these patients require mechanical intubation is a challenge. Serial measurements of maximum inspiratory force and vital capacity are important and can be accomplished quickly at the bedside by a respiratory therapist. A maximum inspiratory force less than –30 cm H₂O or a vital capacity less than 20 mL/kg, or both, are worrisome markers that raise concern for impending ventilatory failure. Serial measurements can detect changes in these values that might indicate the need for elective intubation. In any patient presenting with weakness of the limbs, these measurements are an important step in the initial evaluation.

Myasthenic crisis

Myasthenia gravis is caused by autoantibodies directed against postsynaptic acetylcholine receptors. Patients demonstrate muscle weakness, usually in a proximal pattern, with fatigue, respiratory distress, nasal speech, ophthalmoparesis, and dysphagia. Exacerbations can occur as a response to recent infection, surgery, or medications such as neuromuscular blocking agents or aminoglycosides.

Myasthenic crisis, while uncommon, is a life-threatening emergency characterized by bulbar or respiratory failure secondary to muscle weakness. It can occur in patients already diagnosed with myasthenia gravis or may be the initial manifestation of the disease.^42–49 Intubation and mechanical ventilation are frequently required. Postoperative myasthenic patients in whom extubation has been delayed more than 24 hours should be considered in crisis.⁴⁵

The diagnosis of myasthenia gravis can be made by serum autoantibody testing, electromyography, and nerve conduction studies (with repetitive stimulation) or administration of edrophonium in patients with obvious ptosis.

The mainstay of therapy for myasthenic crisis is either intravenous immunoglobulin at a dose of 2 g/kg over 2 to 5 days or plasmapheresis (5–7 exchanges over 7–14 days). Corticosteroids are not recommended in myasthenic crisis in patients who are not intubated, as they can potentiate an initial worsening of crisis. Once the patient begins to show clinical improvement, outpatient pyridostigmine and immunosuppressive medications can be resumed at a low dose and titrated as tolerated.

Acute inflammatory demyelinating polyneuropathy (Guillain-Barré syndrome)

Acute inflammatory demyelinating polyneuropathy is an autoimmune disorder involving autoantibodies against axons or myelin in the peripheral nervous system.

This disease should be suspected in a patient who is developing worsening muscle weakness (usually with areflexia) over the course of days to weeks. Occasionally, a recent diarrheal or other systemic infectious trigger can be identified. Blood pressure instability and cardiac arrhythmia can also be seen due to autonomic nerve involvement. Although classically described as an “ascending paralysis,” other variants of this disease have distinct clinical presentations (eg, the descending paralysis, ataxia, areflexia, ophthalmoparesis of the Miller Fisher syndrome).

Acute inflammatory demyelinating polyneuropathy is diagnosed by electromyography and nerve conduction studies. A cerebrospinal fluid profile demonstrating elevated protein and few white blood cells is typical.

Treatment, as in myasthenic crisis, involves intravenous immunoglobulin or plasmapheresis. Corticosteroids are ineffective. Anticipation of ventilatory failure and expectant intubation is essential, given the progressive nature of the disorder.⁵⁰

Neurologic emergencies such as acute stroke, status epilepticus, subarachnoid hemorrhage, neuromuscular weakness, and spinal cord injury affect millions of Americans yearly.^1,2 These conditions can be difficult to diagnose, and delays in recognition and treatment can have devastating results. Consequently, it is important for nonneurologists to be able to quickly recognize these conditions and initiate timely management, often while awaiting neurologic consultation.

Here, we review how to recognize and treat these common, serious conditions.

ACUTE ISCHEMIC STROKE: TIME IS OF THE ESSENCE

Stroke is the fourth leading cause of death in the United States and is one of the most common causes of disability worldwide.^3–5 About 85% of strokes are ischemic, resulting from diminished vascular supply to the brain. Symptoms such as facial droop, unilateral weakness or numbness, aphasia, gaze deviation, and unsteadiness of gait may be seen. Time is of the essence, as all currently available interventions are safe and effective only within defined time windows.

Diagnosis and assessment

When acute ischemic stroke is suspected, the clinical history, time of onset, and basic neurologic examination should be obtained quickly.

The National Institutes of Health (NIH) stroke scale is an objective marker for assessing stroke severity as well as evolution of disease and should be obtained in all stroke patients. Scores range from 0 (best) to 42 (worst) (www.ninds.nih.gov/doctors/NIH_Stroke_Scale.pdf).

Time of onset of symptoms is essential to determine, since it guides eligibility for acute therapies. Clinicians should ascertain the last time the patient was seen to be neurologically well in order to estimate this time window as closely as possible.

Laboratory tests should include a fingerstick blood glucose measurement, coagulation studies, complete blood cell count, and basic metabolic profile.

Computed tomography (CT) of the head without contrast should be obtained immediately to exclude acute hemorrhage and any alternative diagnoses that could explain the patient’s symptoms. Acute brain ischemia is often not apparent on CT during the first few hours of injury. Therefore, a patient presenting with new focal neurologic deficits and an unremarkable result on CT of the head should be treated as having had an acute ischemic stroke, and interventional therapies should be considered.

Stroke mimics should be considered and treated, as appropriate (Table 1).

Acute management of ischemic stroke

Acute treatment should not be delayed by obtaining chest radiography, inserting a Foley catheter, or obtaining an electrocardiogram. The longer the time that elapses before treatment, the worse the functional outcome, underscoring the need for rapid decision-making.^6–8

Lowering the head of the bed may provide benefit by promoting blood flow to ischemic brain tissue.⁹ However, this should not be done in patients with significantly elevated intracerebral pressure and concern for herniation.

Permissive hypertension (antihypertensive treatment only for blood pressure greater than 220/110 mm Hg) should be allowed per national guidelines to provide adequate perfusion to brain areas at risk of injury.¹⁰

Tissue plasminogen activator. Patients with ischemic stroke who present within 3 hours of symptom onset should be considered for intravenous administration of tissue plasminogen activator (tPA), a safe and effective therapy with nearly 2 decades of evidence to support its use.¹⁰ The treating physician should carefully review the risks and benefits of this therapy.

To receive tPA, the patient must have all of the following:

• Clinical diagnosis of ischemic stroke with measurable neurologic deficit
• Onset of symptoms within the past 3 hours
• Age 18 or older.

The patient must not have any of the following:

• Significant stroke within the past 3 months
• Severe traumatic head injury within the past 3 months
• History of significant intracerebral hemorrhage
• Previously ruptured arteriovenous malformation or intracranial aneurysm
• Central nervous system neoplasm
• Arterial puncture at a noncompressible site within the past 7 days
• Evidence of hemorrhage on CT of the head
• Evidence of ischemia in greater than 33% of the cerebral hemisphere on head CT
• History and symptoms strongly suggesting subarachnoid hemorrhage
• Persistent hypertension (systolic pressure ≥ 185 mm Hg or diastolic pressure ≥ 110 mm Hg)
• Evidence of acute significant bleeding (external or internal)
• Hypoglycemia—ie, serum glucose less than 50 mg/dL (< 2.8 mmol/L)
• Thrombocytopenia (platelet count < 100 × 10⁹/L)
• Significant coagulopathy (international normalized ratio > 1.7, prothrombin time > 15 seconds, or abnormally elevated activated partial thromboplastin time)
• Current use of a factor Xa inhibitor or direct thrombin inhibitor.

Relative contraindications:

• Minor or rapidly resolving symptoms
• Major surgery or trauma within the past 14 days
• Gastrointestinal or urinary tract bleeding within the past 21 days
• Myocardial infarction in the past 3 months
• Unruptured intracranial aneurysm
• Seizure occurring at stroke onset
• Pregnancy.

If these criteria are satisfied, tPA should be given at a dose of 0.9 mg/kg intravenously over 60 minutes. Ten percent  of the dose should be given as an initial bolus, followed by a constant infusion of the remaining 90% over 1 hour.

If tPA is given, the blood pressure must be kept lower than 185/110 mm Hg to minimize the risk of symptomatic intracerebral hemorrhage.

A subset of patients may benefit from receiving intravenous tPA between 3 and 4.5 hours after the onset of stroke symptoms. These include patients who are no more than 80 years old, who have not recently used oral anticoagulants, who do not have severe neurologic injury (ie, do not have NIH Stroke Scale scores > 25), and who do not have diabetes mellitus or a history of ischemic stroke.¹¹ Although many hospitals have such a protocol for tPA up to 4.5 hours after the onset of stroke symptoms, this time window is not currently approved by the US Food and Drug Administration.

Intra-arterial therapy. Based on recent trials, some patients may benefit further from intra-arterial thrombolysis or mechanical thrombectomy, both delivered during catheter-based cerebral angiography, independent of intravenous tPA administration.^12,13 These patients should be evaluated on a case-by-case basis by a neurologist and neurointerventional team. Time windows for these treatments generally extend to 6 hours from stroke onset and perhaps even longer in some situations (eg, basilar artery occlusion).

An antiplatelet agent should be started quickly in all stroke patients who do not receive tPA. Patients who receive tPA can begin receiving an antiplatelet agent 24 hours afterward.

Unfractionated heparin. There is no evidence to support the use of unfractionated heparin in most cases of acute ischemic stroke.¹⁰

Glucose control (in the range of 140–180 mg/dL) and fever control remain essential elements of post-acute stroke care to provide additional protection to the damaged brain.

For ischemic stroke due to atrial fibrillation

In ischemic stroke due to atrial fibrillation, early anticoagulation should be considered, based on the CHA₂DS₂-VASC risk of ischemic stroke vs the HAS-BLED risk of hemorrhage (calculators available at www.mdcalc.com).

In general, anticoagulation may be withheld during the first 72 hours while further stroke workup and evaluation of extent of injury are carried out, as there is an increased risk of hemorrhagic transformation of the ischemic stroke. Often, anticoagulation is resumed at a full dose between 72 hours and 2 weeks of the ischemic stroke.

ACUTE HEMORRHAGIC STROKE: BLOOD PRESSURE, COAGULATION

Approximately 15% of strokes are caused by intracerebral hemorrhage, which can be detected with noncontrast head CT with a sensitivity of 98.6% within 6 hours of the onset of bleeding.¹⁴ A common underlying cause of intracerebral hemorrhage is chronic poorly controlled hypertension, causing rupture of damaged (or “lipohyalinized”) vessels with resultant blood extravasation into the brain parenchyma. Other causes are less common (Table 2).

Treatment of acute hemorrhagic stroke

Acute treatment of intracerebral hemorrhage includes blood pressure control, reversal of underlying coagulopathy or anticoagulation, and sometimes intracranial pressure control. There is little role for surgery in most cases, based on findings of randomized trials.¹⁵

Blood pressure control. Many studies have investigated optimal blood pressure goals in acute intracerebral hemorrhage. Recent data suggest that early aggressive therapy, targeting a systolic blood pressure goal less than 140 mm Hg within the first hour, is safe and can lead to better functional outcomes than a more conservative blood-pressure-lowering target.¹⁶ Rapid-onset, short-acting antihypertensive agents in intravenous form, such as nicardipine and labetalol, are frequently used. Of note, this treatment strategy for hemorrhagic stroke is in direct contrast to the treatment of ischemic stroke, in which permissive hypertension (blood pressure goal < 220/110 mm Hg) is often pursued.

Reversal of any coagulation abnormalities should be done quickly in intracranial hemorrhage. Warfarin use has been shown to be a strong independent predictor of intracranial hemorrhage expansion, which increases the risk of death.^17,18

Increasingly, agents other than vitamin K or fresh-frozen plasma are being used to rapidly reverse anticoagulation, including prothrombin complex concentrate (available in three- and four-factor preparations) and recombinant factor VIIa. While four-factor prothrombin complex concentrate and recombinant factor VIIa have been shown to be more efficacious than fresh-frozen plasma, there are limited data directly comparing these newer reversal agents against each other.¹⁹ The use of these medications is limited by availability and practitioner familiarity.^20–22

Reversing anticoagulation due to target-specific oral anticoagulants. The acute management of intracranial hemorrhage in patients taking the new target-specific oral anticoagulants (eg, dabigatran, apixaban, rivaroxaban, edoxaban) remains challenging. Laboratory tests such as factor Xa levels are not readily available in many institutions and do not provide results in a timely fashion, and in the interim, acute hemorrhage and clinical deterioration may occur. Management strategies involve giving fresh-frozen plasma, prothrombin complex concentrate, and consideration of hemodialysis.²³ Dabigatran reversal with idarucizumab has recently been shown to have efficacy.²⁴

Vigilance for elevated intracranial pressure. Intracranial hemorrhage can occasionally cause elevated intracranial pressure, which should be treated rapidly. Any acute decline in mental status in a patient with intracranial hemorrhage requires emergency imaging to evaluate for expansion of hemorrhage.

SUBARACHNOID HEMORRHAGE

The sudden onset of a “thunderclap” headache (often described by patients as “the worst headache of my life”) suggests subarachnoid hemorrhage.

In contrast to intracranial hemorrhage, in subarachnoid hemorrhage blood collects mainly in the cerebral spinal fluid-containing spaces surrounding the brain, leading to a higher incidence of hydrocephalus from impaired drainage of cerebrospinal fluid. Nontraumatic subarachnoid hemorrhage is most often caused by rupture of an intracranial aneurysm, which can be a devastating event, with death rates approaching 50%.²⁵

Diagnosis of subarachnoid hemorrhage

Noncontrast CT of the head is the main modality for diagnosing subarachnoid hemorrhage. Blood within the subarachnoid space is demonstrable in 92% of cases if CT is performed within the first 24 hours of hemorrhage, with an initial sensitivity of about 95% within the first 6 hours of onset.^14,26,27 The longer CT is delayed, the lower the sensitivity.

Some studies suggest that a protocol of CT followed by CT angiography can safely exclude aneurysmal subarachnoid hemorrhage and obviate the need for lumbar puncture. However, further research is required to validate this approach.²⁸

Lumbar puncture. If clinical suspicion of subarachnoid hemorrhage remains strong even though initial CT is negative, lumbar puncture must be performed for cerebrospinal fluid analysis.²⁹ Xanthochromia (a yellowish pigmentation of the cerebrospinal fluid due to the degeneration of blood products that occurs within 8 to 12 hours of bleeding) should raise the alarm for subarachnoid hemorrhage; this sign may be present up to 4 weeks after the bleeding event.³⁰

If lumbar puncture is contraindicated, then aneurysmal subarachnoid hemorrhage has not been ruled out, and further neurologic consultation should be pursued.

Management of subarachnoid hemorrhage

Early management of blood pressure for a ruptured intracranial aneurysm follows strategies similar to those for intracranial hemorrhage. Further investigation is rapidly directed toward an underlying vascular malformation, with intracranial vessel imaging such as CT angiography, magnetic resonance angiography, or the gold standard test—catheter-based cerebral angiography.

Aneurysms are treated (or “secured”) either by surgical clipping or by endovascular coiling. Endovascular coiling is preferable in cases in which both can be safely attempted.³¹ If the facility lacks the resources to do these procedures, the patient should be referred to a nearby tertiary care center.

INTRACRANIAL HYPERTENSION: DANGER OF BRAIN HERNIATION

A number of conditions can cause an acute intracranial pressure elevation. The danger of brain herniation requires that therapies be implemented rapidly to prevent catastrophic neurologic injury. In many situations, nonneurologists are the first responders and therefore should be familiar with basic intracranial pressure management.

Initial symptoms of acute rise in intracranial pressure

As intracranial pressure rises, pressure is typically equally distributed throughout the cranial vault, leading to dysfunction of the ascending reticular activating system, which clinically manifests as the inability to stay alert despite varying degrees of noxious stimulation. Progressive cranial neuropathies (often starting with pupillary abnormalities) and coma are often seen in this setting as the upper brainstem begins to be compressed.

Initial assessment and treatment of elevated intracranial pressure

Noncontrast CT of the head is often obtained immediately when acutely elevated intracranial pressure is suspected. If clinical examination and radiographic findings are consistent with intracranial hypertension, prompt measures can be started at the bedside.

Elevate the head of the bed to 30 degrees to promote venous drainage and reduce intracranial pressure. (In contrast, most other hemodynamically unstable patients are placed flat or in the Trendelenburg position.)

Intubation should be done quickly in cases of airway compromise, and hyperventilation should be started with a goal Paco₂ of 30 to 35 mm Hg. This hypocarbic strategy promotes cerebral vasoconstriction and a transient decrease in intracranial pressure.

Hyperosmolar therapy allows for transient intracranial volume decompression and is the mainstay of emergency medical treatment of intracranial hypertension. Mannitol is a hyper­osmolar polysaccharide that promotes osmotic diuresis and removes excessive cerebral water. In the acute setting, it can be given as an intravenous bolus of 1 to 2 g/kg through a peripheral intravenous line, followed by a bolus every 4 to 6 hours. Hypotension can occur after diuresis, and renal function should be closely monitored since frequent mannitol use can promote acute tubular necrosis. In patients who are anuric, the medication is typically not used.

Hypertonic saline (typically 3% sodium chloride, though different concentrations are available) is an alternative that helps draw interstitial fluid into the intravascular space, decreasing cerebral edema and maintaining hemodynamic stability. Relative contraindications include congestive heart failure or renal failure leading to pulmonary edema from volume overload. Hypertonic saline can be given as a bolus or a constant infusion. Some institutions have rapid access to 23.4% saline, which can be given as a 30-mL bolus but typically requires a central venous catheter for rapid infusion.

Comatose patients with radiographic findings of hydrocephalus, epidural or subdural hematoma, or mass effect with midline shift warrant prompt neurosurgical consultation for further surgical measures of intracranial pressure control and monitoring.

The ‘blown’ pupil

The physician should be concerned about elevated intracranial pressure if a patient has mydriasis, ie, an abnormally dilated (“blown”) pupil, which is a worrisome sign in the setting of true intracranial hypertension. However, many different processes can cause mydriasis and should be kept in mind when evaluating this finding (Table 3).³² If radiographic findings do not suggest elevated intracranial pressure, further workup into these other processes should be pursued.

STATUS EPILEPTICUS: SEIZURE CONTROL IS IMPORTANT

A continuous unremitting seizure lasting longer than 5 minutes or recurrent seizure activity in a patient who does not regain consciousness between seizures should be treated as status epilepticus. All seizure types carry the risk of progressing to status epilepticus, and responsiveness to antiepileptic drug therapy is inversely related to the duration of seizures. It is imperative that seizure activity be treated early and aggressively to prevent recalcitrant seizure activity, neuronal damage, and progression to status epilepticus.³³

Once the ABCs of emergency stabilization have been performed (ie, airway, breathing, circulation), antiepileptic drug therapy should start immediately using established algorithms (Figure 1).^34–36 During the course of treatment, the reliability of the neurologic examination may be limited due to medication effects or continued status epilepticus, making continuous video electroencephalographic monitoring often necessary to guide further therapy in patients who are not rapidly recovering.^34–38

Once status epilepticus has resolved, further investigation into the underlying cause should be pursued quickly, especially in patients without a previous diagnosis of epilepsy. Head CT with contrast or magnetic resonance imaging can be used to look for any structural abnormality that may explain seizures. Basic laboratory tests including toxicology screening can identify a common trigger such as hypoglycemia or stimulant use. Fever or other possible signs of meningitis should be investigated further with cerebrospinal fluid analysis.

SPINAL CORD INJURY

Acute spinal cord injury can lead to substantial long-term neurologic impairment and should be suspected in any patient presenting with focal motor loss, sensory loss, or both with sparing of the cranial nerves and mental status. Causes of injury include compression (traumatic or nontraumatic) and inflammatory and noninflammatory myelopathies.

The location of the injury can be inferred by analyzing the symptoms, which can point to the cord level and indicate whether the anterior or posterior of the cord is involved. Anterior cord injury tends to affect the descending corticospinal and pyramidal tracts, resulting in motor deficits and weakness. Posterior cord injury involves the dorsal columns, leading to deficits of vibration sensation and proprioception. High cervical cord injuries tend to involve varying degrees of quadriparesis, sensory loss, and sometimes respiratory compromise. A clinical history of bilateral lower-extremity weakness, a “band-like” sensory complaint around the lower chest or abdomen, or both, can suggest thoracic cord involvement. Symptoms isolated to one or both lower extremities along with lower back pain and bowel or bladder involvement may point to injury of the lumbosacral cord.

Basic management of spinal cord injury includes decompression of the bladder and initial protection against further injury with a stabilizing collar or brace.

Magnetic resonance imaging with and without contrast is the ideal study to evaluate injuries to the spinal cord itself. While CT is helpful in identifying bony disease of the spinal column (eg, evaluating traumatic fractures), it is not helpful in viewing intrinsic cord pathology.

Traumatic myelopathy

Traumatic spinal cord injury is usually suggested by the clinical history and confirmed with CT. In this setting, early consultation with a neurosurgeon is required to prevent permanent cord injury.

Guidelines suggest maintaining a mean arterial pressure greater than 85 to 90 mm Hg for the first 7 days after traumatic spinal cord injury, a particular problem in the setting of hemodynamic instability, which can accompany lesions above the midthoracic level.^39,40

Patients with vertebral body misalignment should be placed in an appropriate stabilizing collar or brace until a medically trained professional deems it appropriate to discontinue the device, or until surgical stabilization is performed.

Methylprednisone is a controversial intervention for acute spinal cord trauma, lacking clear benefit in meta-analyses.⁴¹

Nontraumatic compressive myelopathy

Patients with nontraumatic compressive myelopathy tend to present with varying degrees of back pain and worsening sensorimotor function. The differential diagnosis includes epidural abscesses, hematoma, metastatic neoplasm, and osteophyte compression (Table 4). The clinical history helps to guide therapy and should involve assessment for previous spinal column injury, immunocompromised state, travel history (which provides information on risks of exposure to a variety of diseases, including infections), and constitutional symptoms such as fever and weight loss.

Epidural abscess can have devastating results if missed. Red flags such as recent illness, intravenous drug use, focal back pain, fever, worsening numbness or weakness, and bowel or bladder incontinence should raise suspicion of this disorder. Emergency magnetic resonance imaging is required to diagnose this condition, and treatment involves urgent administration of antibiotics and consideration of surgical drainage.

Noncompressive myelopathies

There are numerous causes of noncompressive spinal cord injury (Table 4), and the etiology may be inflammatory (eg, “myelitis”) or noninflammatory. The diagnostic workup may require both magnetic resonance imaging and cerebrospinal fluid analysis. Acute disease-targeted therapy is rarely indicated and can be deferred until a full diagnostic workup has been completed.

NEUROMUSCULAR DISEASE: IS VENTILATION NEEDED?

Diseases involving the motor components of the peripheral nervous system (Table 5) share the common risk of causing ventilatory failure due to weakness of the diaphragm, intercostal muscles, and upper-airway muscles. Clinicians need to be aware of this risk and view these disorders as neurologic emergencies.

Determining when these patients require mechanical intubation is a challenge. Serial measurements of maximum inspiratory force and vital capacity are important and can be accomplished quickly at the bedside by a respiratory therapist. A maximum inspiratory force less than –30 cm H₂O or a vital capacity less than 20 mL/kg, or both, are worrisome markers that raise concern for impending ventilatory failure. Serial measurements can detect changes in these values that might indicate the need for elective intubation. In any patient presenting with weakness of the limbs, these measurements are an important step in the initial evaluation.

Myasthenic crisis

Myasthenia gravis is caused by autoantibodies directed against postsynaptic acetylcholine receptors. Patients demonstrate muscle weakness, usually in a proximal pattern, with fatigue, respiratory distress, nasal speech, ophthalmoparesis, and dysphagia. Exacerbations can occur as a response to recent infection, surgery, or medications such as neuromuscular blocking agents or aminoglycosides.

Myasthenic crisis, while uncommon, is a life-threatening emergency characterized by bulbar or respiratory failure secondary to muscle weakness. It can occur in patients already diagnosed with myasthenia gravis or may be the initial manifestation of the disease.^42–49 Intubation and mechanical ventilation are frequently required. Postoperative myasthenic patients in whom extubation has been delayed more than 24 hours should be considered in crisis.⁴⁵

The diagnosis of myasthenia gravis can be made by serum autoantibody testing, electromyography, and nerve conduction studies (with repetitive stimulation) or administration of edrophonium in patients with obvious ptosis.

The mainstay of therapy for myasthenic crisis is either intravenous immunoglobulin at a dose of 2 g/kg over 2 to 5 days or plasmapheresis (5–7 exchanges over 7–14 days). Corticosteroids are not recommended in myasthenic crisis in patients who are not intubated, as they can potentiate an initial worsening of crisis. Once the patient begins to show clinical improvement, outpatient pyridostigmine and immunosuppressive medications can be resumed at a low dose and titrated as tolerated.

Acute inflammatory demyelinating polyneuropathy (Guillain-Barré syndrome)

Acute inflammatory demyelinating polyneuropathy is an autoimmune disorder involving autoantibodies against axons or myelin in the peripheral nervous system.

This disease should be suspected in a patient who is developing worsening muscle weakness (usually with areflexia) over the course of days to weeks. Occasionally, a recent diarrheal or other systemic infectious trigger can be identified. Blood pressure instability and cardiac arrhythmia can also be seen due to autonomic nerve involvement. Although classically described as an “ascending paralysis,” other variants of this disease have distinct clinical presentations (eg, the descending paralysis, ataxia, areflexia, ophthalmoparesis of the Miller Fisher syndrome).

Acute inflammatory demyelinating polyneuropathy is diagnosed by electromyography and nerve conduction studies. A cerebrospinal fluid profile demonstrating elevated protein and few white blood cells is typical.

Treatment, as in myasthenic crisis, involves intravenous immunoglobulin or plasmapheresis. Corticosteroids are ineffective. Anticipation of ventilatory failure and expectant intubation is essential, given the progressive nature of the disorder.⁵⁰