Neurology of systemic disease

Question 1

Neurological complications of IE

Answer 1

Stroke (MC)
intracranial hemorrhage (most often due to hemorrhagic conversion of an ischemic infarct), subarachnoid hemorrhage, cerebral abscess, meningoencephalitis, and seizures. Headaches and encephalopathy also occur, often as a symptom of the latter complications.
Septic cerebral emboli -\> to mycotic aneurysms by causing intraluminal arterial wall necrosis (due to arteritis) and destruction of the adventitia and muscularis with subsequent dilatation. Mycotic aneurysms - more distal, at distal arterial bifurcations, best detected by conventional cerebral angiography.
Mainstay of therapy for the neurologic complications: antibiotic therapy and acute symptomatic management (such as AEDs in patients with seizures). In certain cases of mycotic aneurysms, endovascular embolization or surgical resection may be indicated, especially in the setting of acute hemorrhage, and those patients requiring anticoagulation and/or open heart surgery.
Neurologic complications occur in both patients with native and prosthetic valve endocarditis in a similar proportion. 
In those with prosthetic valves, those with mechanical valves may have more complications than those with bioprosthetic valves.
 Left-sided endocarditis is associated with higher risk of neurologic complications as compared to right-sided cases.

Question 2

Neurological complications of sickle cell disease

Answer 2

MC in SS than SC
Neurological complications: ischemic stroke, intracranial hemorrhage, cranial neuropathies, spinal cord infarction (although rare), intracranial aneurysm formation with subarachnoid hemorrhage, ischemic optic neuropathy, optic atrophy, seizures, and headaches.
Ischemic stroke is more common in children with Hb SS disease than in adults.
In children, transcranial Doppler ultrasonography should be periodically performed, and when elevated velocities are detected, blood transfusion (or exchange transfusion) have been shown to reduce the risk of ischemic stroke. Blood transfusions or exchange transfusions are used with the goal of reducing the percentage of hemoglobin S, therefore reducing the percentage of red blood cells that can sickle.

The pathophysiology of ischemic strokes in these patients is not completely understood, with sickling and increased viscosity likely playing a significant role. However, large-vessel intracranial stenosis and/or occlusions are also frequently encountered, sometimes with Moyamoya-like appearance.

Question 3

Plasma cell dycrasias

Answer 3

Include: Waldenström macroglobulinemia (smoldering or symptomatic), monoclonal gammopathy of unknown significance (MGUS), multiple myeloma (smoldering or symptomatic), plasmacytomas (bone and extramedullary), primary amyloidosis, idiopathic Bence Jones proteinuria, etc. Neurological complications: neuropathy (2/2 infiltration of the peripheral nervous system by abnormal cells, amyloidosis, or a paraneoplastic syndrome) Infiltration of peripheral nerves would typically cause a sensorimotor predominantly axonal neuropathy. Infiltration of vertebral bodies can be extensive enough to lead to nerve root as well as spinal cord compression. Patients with plasma cell dyscrasias may develop encephalopathy due to hypercalcemia, hyperviscosity syndrome (due to hypergammaglobulinemia), and CNS infections, which such patients are prone to due to their immunocompromised state. Direct CNS involvement in plasma cell dyscrasias can occur but is relatively rare. POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) is a constellation of abnormalities seen in some patients with plasma cell dyscrasias, particularly plasmacytoma, and not with leukemias.

Question 4

anti-MAG

Answer 4

Patients with MGUS (which is characterized by the presence of a monoclonal protein in the absence of significant bone marrow involvement, anemia, renal failure, lytic lesions, or hypercalcemia) are at risk of developing symptomatic multiple myeloma. However, MGUS without evidence of other hematologic disorders can be associated with neuropathy. The neuropathy is often primarily demyelinating, and in some cases, particularly in patients with IgM MGUS, antibodies against MAG are detected in the serum.

Question 5

Neuropathy in patients with monoclonal proteinemias, with cryoglobulin

Answer 5

Cryoglobulins are serum protein complexes that precipitate at specific temperatures. They occur in a variety of conditions as follows:

• Type I cryoglobulins are isolated monoclonal proteins (usually IgM) seen in the monoclonal paraproteinemias such as multiple myeloma and Waldenström macroglobulinemia.
• Type II cryoglobulins are polyclonal immunocomplexes (formed by monoclonal IgM and IgG), usually seen in lymphoproliferative and autoimmune disorders, and Hepatitis C virus infection.
• Type III cryoglobulins are polyclonal immunocomplexes (formed by polyclonal IgM and IgG) seen with underlying infectious and autoimmune disorders (e.g., systemic lupus erythematosus and rheumatoid arthritis). The most common neuropathic complication of cryoglobulinemia is generalized neuropathy, although mononeuritis or mononeuritis multiplex and cerebral vasculitis with ischemic stroke can also occur.

Question 6

TTP

Answer 6

The diagnostic pentad of TTP includes a microangiopathic hemolytic anemia, low platelet counts, renal dysfunction, neurologic signs or symptoms, and fever, although not all five features may necessarily be present. TTP results from a deficiency of von Willebrand factor– cleaving protease, leading to abnormal platelet aggregation. Neurologic manifestations include seizures, headaches, encephalopathy, and in severe cases coma, cranial neuropathies, and focal neurologic deficits. Treatment includes emergency plasma exchange.

Vs HUS: HUS is associated with more severe renal function, predominantly a disorder of childhood, often associated with an infection with Shiga toxin–producing bacteria such as certain strains of Escherichia coli and Shigella; typically preceded by abdominal pain and diarrhea; aeizures, encephalopathy, cranial nerve palsies, and neuropathy may occur.

Vs DIC: Platelet counts and schistocytes in both, DIC with elevated D-dimer, reduced fibrinogen, and increased clotting time which are normal in TTP

Question 7

Hepatic encephalopathy

Answer 7

Clinical manifestations are variable, ranging from mildly decreased attention, disorientation, and personality changes to somnolence and in severe cases coma. Asterixis, or negative myoclonus, is seen in hepatic encephalopathy and other metabolic encephalopathies. EEG findings include generalized slowing and triphasic waves.

Serum ammonia levels may be elevated, but hepatic encephalopathy may occur even at relatively low serum ammonia levels, due to the impaired cerebral ammonia uptake and metabolism seen in patients with cirrhosis. Clinical improvement in mental status is the best indicator of response to therapy, and serum ammonia concentrations are not reliable for this purpose. Treatment of hepatic encephalopathy includes correction of precipitating factors (hypovolemia, gastrointestinal bleed, infection, and others), instituting a low-protein diet, and reduction of ammonia absorption from the colon by using the disaccharide lactulose, sometimes in combination with the antibiotics rifaximin or neomycin.

The pathologic hallmark of hepatic encephalopathy is the Alzheimer type II astrocyte, which is seen in various areas of the cortex and subcortical regions, including the basal ganglia, thalamus, dentate of the cerebellum, and red nuclei.

Pathophysiology: Ammonia is normally produced in the colon and is taken to the liver through the hepatic portal vein, where it is converted to urea and excreted in the urine. With liver dysfunction, ammonia and other toxic substances are shunted to the systemic circulation (the so-called portosystemic shunting). Transjugular intrahepatic portosystemic shunt, used to treat certain complications of portal hypertension (such as recurrent esophageal variceal hemorrhage), increases the risk of hepatic encephalopathy, as it enhances shunting of ammonia to the systemic circulation.

Hyperammonemia, abnormal GABA and glutamate neurotransmission, and abnormalities in fatty acids.

Question 8

Celiac disease

Answer 8

Celiac disease, also known as gluten- sensitive enteropathy, results from an immune-mediated intolerance to gluten, a protein found in foods containing cereal grains. Chronic diarrhea with malabsorption is common, and small- bowel biopsy shows atrophy of intestinal villi. Celiac disease can have a variety of neurologic manifestations; in fact, neurologic manifestations may be the only clinical features in a minority of patients. These include a predominantly axonal peripheral neuropathy, inflammatory myopathy, cerebral calcifications, and seizures. Prominent cerebellar involvement is often seen because of loss of Purkinje cells in the cerebellum. The mainstay of treatment is a gluten-free diet, although some of the neurologic manifestations, such as ataxia resulting from cerebellar atrophy, may not be reversible. Patients with celiac disease can also have neurologic complications resulting from vitamin E deficiency (discussed in Chapter 17) due to chronic malabsorption.

Vs Whipple’s disease secondary to Tropheryma whipplei.: ulfonamides are used for the treatment of Whipple disease rather than celiac disease; absence of periodic acid-Schiff–positive macrophage inclusions on bowel biopsy makes Whipple disease less likely

Question 9

Neurological manifestations of renal failure

Answer 9

Patients with renal failure can have a variety of neurologic signs and symptoms. Alteration in awareness from renal failure or uremic encephalopathy may manifest as reduced alertness, poor attention and concentration, perceptual errors, and hallucinations. In more severe cases, the patient may be unable to interact with the environment or even be comatose. Patients with uremic encephalopathy, as with other metabolic encephalopathies, may exhibit multiple motor symptoms including asterixis, myoclonus (the so-called uremic twitching, attributed to alterations in cerebral phosphate metabolism), and gait ataxia. Seizures can occur in both acute and chronic renal failure. When treating seizures in patients with renal failure, attention must be given to the pharmacokinetic changes that occur in such patients. Uremic neuropathy is typically a distal, generalized symmetric sensorimotor axonal polyneuropathy. Mononeuropathies can occur as a complication of arteriovenous shunt placement.

Question 10

Dialysis disequilibrium syndrome

Answer 10

Dialysis disequilibrium syndrome is a spectrum of neurologic signs and symptoms occurring during or after dialysis. It is most common during initiation of urgent dialysis but may occur at any time. It is thought to result at least in part from shifts of water into the brain due to changes in the osmotic gradient. Clinical manifestations can range from mild encephalopathy to fatal cerebral edema. Symptoms persist for hours or days after dialysis. Other neurologic manifestations in patients with renal failure include dementia and restless legs syndrome.

Question 11

Hypo/hyperglycemia

Answer 11

Hypoglycemia may cause temporary focal deficits simulating stroke. Hyperglycemia, usually in the setting of a nonketotic hyperosmolar syndrome, may also cause focal neurologic symptoms. Other metabolic abnormalities do not typically cause focal deficits.

Question 12

Hypo/hypernatremia

Answer 12

Hyponatremia typically causes more severe neurologic symptoms when it develops rapidly, but symptoms can also occur with chronic hyponatremia. A nonspecific encephalopathy is the most frequent manifestation. Seizures can occur with acute hyponatremia, usually with serum sodium levels of 115 mEq/L or less. Correction of serum sodium levels is the mainstay of treatment of hyponatremia-associated seizures, but care must be taken not to correct serum sodium levels too rapidly, given the risk of central pontine myelinolysis (discussed in Chapter 3). The rate of correction of hyponatremia should be no more than 12 mEq/L per day, or 0.5 mEq/L per hour.

CNS manifestations of hypernatremia typically occur with serum sodium concentrations higher than 160 mEq/L and include encephalopathy, seizures, and in severe cases coma.

Question 13

Hypokalemia and hyperkalemia

Answer 13

Both hypokalemia and hyperkalemia are associated with peripheral rather than CNS manifestations. Hypokalemia can lead to myalgia and proximal limb weakness (with sparing of bulbar muscles). Rhabdomyolysis can occur with severe hypokalemia. Tetany may be a manifestation of hypokalemia (or hypocalcemia). _Hyperkalemia is associated with muscle weakness in the context of hyperkalemic periodic paralysis or Addison disease, but rarely otherwis_e.

Question 14

Hyper and hypocalcemia

Answer 14

Neurologic manifestations of hypercalcemia include encephalopathy and in severe cases coma. Other manifestations include headache and rarely seizures. Hyperparathyroidism can lead to depression, encephalopathy, and myopathy.

Seizures are a much more common complication of hypocalcemia. Hypocalcemia also leads to tetany, which is due to spontaneous repetitive nerve action potentials. Initial symptoms of hypocalcemia include tingling in the perioral area and the digits. In more severe later stages, tonic muscle spasms occur, beginning in the fingers and toes (carpopedal spasm) but in some cases involving more proximal musculature; when the tetany involves truncmusculature, opisthotonos is present.

Question 15

Hypo/hypermagnesium

Answer 15

Hypomagnesemia can lead to encephalopathy, tremor, myoclonus, and in severe cases seizures. Hypermagnesemia is rare, usually occurring in the setting of renal failure. Neurologic manifestations of severe hypermagnesemia include areflexia/hyporeflexia, and muscle weakness that when severe may progress to respiratory failure.

Question 16

Hypo/hypermagnesium

Answer 16

Hypomagnesemia can lead to encephalopathy, tremor, myoclonus, and in severe cases seizures. Hypermagnesemia is rare, usually occurring in the setting of renal failure. Neurologic manifestations of severe hypermagnesemia include areflexia/hyporeflexia, and muscle weakness that when severe may progress to respiratory failure.

Question 17

Thyroid function in encephalopathy

Answer 17

In a patient presenting with cognitive dysfunction, apathy, and hypersomnolence, hypothyroidism is a diagnostic possibility, and serum thyroid-stimulating hormone (TSH) level should be tested.

Antimicrosomal antibodies are also checked in patients with a relapsing–remitting encephalopathy or with other neurologic manifestations that raise concern for steroid- responsive encephalopathy with autoimmune thyroiditis (SREAT or Hashimoto encephalopathy).

Question 18

Tremor in thyroid disease

Answer 18

Tremor is almost universally present in patients with untreated hyperthyroidism. It is typically a postural, high-frequency tremor that is thought to result from increased β-adrenergic activity.

Other abnormal movements seen in patients with hyperthyroidism include parkinsonism, dyskinesia, chorea, and myoclonus. Pseudomyotonia, or a delay in muscle relaxation following elicitation of deep tendon reflex, is a feature of hypothyroidism.

Both hypothyroidism and hyperthyroidism can lead to myopathy. Serum creatine kinase level is typically elevated. Gait dysfunction in patients with thyroid disorders could be due to cerebellar ataxia, myopathy, neuropathy, or a combination of these.

Congenital hypothyroidism is the most treatable cause of mental retardation. Untreated, it leads to cretinism, which is manifested by cognitive dysfunction, gait dysfunction, and hearing loss. The most common cause is dysgenesis of the thyroid, but severe maternal iodine deficiency also can lead to it.

Thyroid eye disease in patients with Graves’ disease results from an immune-mediated increase in connective tissue of the orbit. Manifestations include proptosis, extraocular muscle enlargement with restricted movement, optic nerve compression, and ocular neuromyotonia. Restricted upward gaze is the most common extraocular abnormality seen in patients with thyroid eye disease, but impaired abduction, adduction, and downward gaze also occur. Eyelid retraction in patients with Graves’ disease may be due to overactivation of Muller muscle (a sympathetically innervated muscle) or eyelid fibrosis.

Myxedema coma, due to severe untreated hypothyroidism, typically occurs in older adults and is often precipitated by intercurrent illnesses. Clinical features include hypothermia and encephalopathy. Seizures occur in some patients.

Patients with hypothyroidism may develop diffuse peripheral neuropathy with both axonal and/or demyelinating features and entrapment neuropathy, most commonly carpal tunnel syndrome, resulting from deposition of mucopolysaccharides.
Other neurologic manifestations of thyroid disease include bothobstructive and central sleep apnea, headache, and hearing impairment with tinnitus

Question 19

Diabetic neuropathy

Answer 19

Peripheral nervous system complications of diabetes include small- and large-fiber neuropathy, autonomic neuropathy, radiculopathy (including thoracic radiculopathy), cranial neuropathies (most commonly, cranial nerves III and VI, but may involve others), and diabetic amyotrophy.

Diabetic polyneuropathy occurs in more than half of the patients with diabetes. It is pathophysiologically complex but is in part related to increased activity of the aldose reductase pathway, which leads to accumulation of intraneuronal sorbitol and fructose with subsequent impairment in intracellular signaling, impaired autooxidation of glucose, accumulation of advanced glycation end products, oxidative stress, and impaired neuronal microvascular function.

Early in diabetes, small nerve fibers are predominantly affected, leading to positive sensory symptoms such as tingling and pain. Large-fiber involvement may also lead to positive sensory symptoms, although later in the disease, sensory loss predominates. Diabetic polyneuropathy is most commonly a distal, symmetric, sensorimotor polyneuropathy. Sensory loss is the most common clinical manifestation of diabetic polyneuropathy; motor weakness typically occurs only in advanced cases or from other complications of diabetes. With involvement of nociceptive fibers, injuries may be painless, with the development of painless ulcers that often heal poorly, as in the case depicted in this question. Charcot joints, or relatively painless progressive deformities of the foot and ankle, also occur. Autonomic neuropathy is common in diabetics and can result in a variety of abnormalities including impotence, bladder dysfunction, abnormal pupillary reaction, orthostatic hypotension, and gastroparesis.

Neuropathy can result from impaired glucose tolerance alone inpatients not otherwise meeting laboratory criteria for diabetes. In fact, impaired glucose tolerance is often found in patients with otherwise idiopathic neuropathy, and treatment including diet and exercise may halt progression of the neuropathy. D_iabetic polyneuropathy is irreversible, but slowing the progression is accomplished by adequate glycemic control. Painful neuropathy is treated with medications including nonsteroidal anti-inflammatory agents, antidepressants (tricyclic antidepressants, selective serotonin reuptake inhibitors, norepinephrine serotonin reuptake inhibitors), anticonvulsants (gabapentin and pregabalin), and topical agents such as capsaicin_.

Diabetic oculomotor palsy may present acutely and be associated with ipsilateral forehead pain. It results from ischemia to the third nerve; pupillomotor fibers are spared, given their more circumferential location, distinguishing it from other causes of acute oculomotor palsy such as cerebral aneurysms. Other cranial nerve palsies, particularly VI and VII, can occur in diabetes.

CNS complications of diabetes may result from diabetic ketoacidosis and hyperosmolar hyperglycemic state, both of which can lead to encephalopathy and in severe cases stupor and coma. Cerebrovascular disease due to atherosclerosis and arteriosclerosis due to frequently comorbid hypertension can lead to various CNS manifestations resulting from ischemic stroke. Acute and sometimes permanent chorea can occur in patients with nonketotic hyperglycinemia.

Question 20

Cushing’s disease

Answer 20

Results from hypercortisolism in the setting of an ACTH-secreting pituitary adenoma. Neurologic manifestations of Cushing disease include headache, proximal myopathy, cognitive dysfunction, and behavioral changes, with psychosis in severe cases.

In this patient, the bitemporal hemianopia is a clue to a compressive lesion of the optic chiasm, distinguishing Cushing disease from Cushing syndrome, which can result from cortisol- secreting tumors or from ectopic ACTH production as can occur with paraneoplastic syndromes or other causes.

Hypocortisolism, as occurs in primary adrenal insufficiency or Addison disease, can lead to fatigue, cognitive dysfunction, myopathic weakness, and psychiatric symptoms, but typically not weight gain. Skin manifestations in Addison disease include hyperpigmentation.

Question 21

Osteopetrosis

Answer 21

A sclerosing bone disorder characterized by pathologically increased bone mass due to impaired bone resorption by osteoclasts. It is caused by a mutation in an ATPase or a chloride channel. Autosomal dominant and recessive forms exist, each differing in their age at presentation and clinical manifestations. Some of the younger-onset forms are severe. The majority of patients are asymptomatic, but symptoms may include bone pain, joint deformities, secondary osteoarthritis, and fractures. Many adults with osteopetrosis are asymptomatic, but cranial neuropathies may occur because of skull thickening with subsequent narrowing of cranial nerve (CN) foramina in the base of the skull. The most commonly involved CNs are CN II (in some cases leading to optic atrophy with blindness), VII, and VIII, leading to irreversible hearing loss, as in this patient. Elevated serum alkaline phosphatase level is a clue to this diagnosis. The olfactory nerve is also commonly involved.

A bone disorder with similar neurologic complications to osteopetrosis is Paget disease. Paget disease results from excessive bone turnover and abnormal compensatory bone formation. It is often asymptomatic and diagnosed incidentally, but it may also result in cranial neuropathies (most commonly CN VIII, but also CN II), spinal stenosis with resulting myelopathy, radiculopathy, or a combination of these. Serum alkaline phosphatase level is also elevated in Paget disease.

Question 22

Achrondroplasia

Answer 22

Achondroplasia is an autosomal dominant bone dysplasia characterized by short stature. Cognition often develops normally, but in some, developmental delay may be present. Other neurologic complications include cervical myelopathy due to craniocervical junction abnormalities, radiculopathy, and hydrocephalus.

Question 23

Ankylosing spondylitis

Answer 23

Ankylosing spondylitis is a chronic polyarticular inflammatory disorder that involves the spine and sacroiliac joints. Uveitis and aortic insufficiency may occur. Neurologic complications include vertebral fracture with secondary spinal cord injury and spinal stenosis, leading to radiculopathy and/or myelopathy. Cauda equina syndrome may occur.

Question 24

Relapsing polychondriti

Answer 24

Relapsing polychondritis results from recurrent episodes of inflammation and destruction of cartilage. Episodes commonly involve not only the ears but also the upper airway. Neurologic manifestations include vertigo and hearing loss due to involvement of the vestibulocochlear system. Ocular motor palsies and optic neuritis may rarely occur. Other neurologic manifestations of relapsing polychondritis include cerebral vasculitis, peripheral neuropathy, and aseptic meningitis.

Question 25

SLE

Answer 25

This is an autoimmune disorder characterized by multiorgan involvement and presence of various antibodies including a_nti–double-stranded DNA and anti-Smith antigen_. There are specific diagnostic criteria based on hematologic, dermatologic, neurologic, renal, cardiac, and serologic features.

SLE may involve both the CNS and the peripheral nervous system. Neuropsychiatric manifestations of SLE include cognitive dysfunction, depression, anxiety, and psychosis. Headaches and seizures are among the most common neurologic manifestations; others include aseptic meningitis (as is likely the case in this patient), chorea, and myelopathy. There is an increased risk of ischemic strokes due to a variety of mechanisms including cardioembolism, antiphospholipid antibody–associated thrombosis, premature intracranial atherosclerosis, and rarely secondary cerebral vasculitis. Intracerebral hemorrhage may also occur. Peripheral nervous system manifestations include cranial neuropathies, peripheral mononeuropathy or mononeuritis multiplex, demyelinating or axonal polyneuropathy, and plexopathy.

Question 26

Systemic sclerosis

Answer 26

Systemic sclerosis is a multiorgan disorder that leads to fibrosis. Scleroderma is the term used to describe the skin thickening that is seen in this disorder. Subcutaneous calcinosis, Raynaud phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia (CREST) syndrome is seen in some patients with systemic sclerosis. The diagnosis is made on the basis of the presence of clinical features and antibodies against centromeres and topoisomerases. Intracerebral vasculopathy leading to TIAs, ischemic stroke, or intracranial hemorrhage may occur. Peripheral nervous system manifestations include carpal tunnel syndrome, trigeminal neuropathy, peripheral polyneuropathy, and mononeuritis multiplex.

Question 27

Diagnosis of Sjogren’s syndrome

Answer 27

Sjögren syndrome is an inflammatory multiorgan disorder primarily affecting exocrine glands (such as the salivary and lacrimal glands), leading to xerostomia and xerophthalmia (which when severe can lead to keratoconjunctivitis sicca). Sjögren syndrome often co-occurs with other autoimmune disorders. Constitutional symptoms are often present.

Peripheral nervous system involvement in Sjögren syndrome manifests most commonly as a distal predominantly sensory or mixed sensorimotor axonal polyneuropathy. A sensory neuronopathy, or dorsal root ganglionopathy, as depicted in this case, may occur, and results from involvement of the dorsal root ganglia. With sensory neuronopathy, the sensory loss may not follow a length-dependent pattern but rather can affect the face or trunk before distal segments of the limbs (discussed further in Chapter 9). Sensory ataxia is often prominent in such cases. Other manifestations of Sjögren syndrome include isolated small-fiber neuropathy (without large-fiber involvement), autonomic neuropathy, and cranial neuropathy. CNS manifestations of Sjögren syndrome are uncommon but include cognitive dysfunction, focal brain lesions most often affecting subcortical white matter, aseptic meningitis, optic neuritis, and myelopathy.

Diagnosis is made on the basis of the presence of symptoms of xerostomia and xerophthalmia: abnormal dryness of the conjunctiva and cornea of the eye, with inflammation and ridge formation, typically associated with vitamin A deficiency, objective documentation of xerophthalmia with Schirmer test: https://www.mountsinai.org/health-library/tests/schirmer-test, serologic testing for the autoantibodies anti-Ro (SSA) or anti-La (SSB), and/or minor salivary gland biopsy. Treatment is a combination of symptomatic therapies and immunosuppressants in some cases.

*Rectal biopsy is used to diagnose amyloidosis and is not helpful in the diagnosis of Sjögren syndrome.

Question 28

Alanto-axial dislocation

Answer 28

Atlanto-axial dislocation is most common in patients with rheumatoid arthritis, a polyarticular symmetric inflammatory disorder. In addition to an inflammatory arthritis, other features include subcutaneous nodules, hypersplenism, amyloidosis, scleritis, cardiac, and pulmonary involvement. Diagnosis is made on the basis of the presence of clinical features, rheumatoid factor, and cyclic citrullinated peptide. Atlanto-axial dislocation in rheumatoid arthritis results from inflammation and resulting laxity of the ligaments, with pannus formation. Myelopathy may also occur. The most common neurologic manifestation of rheumatoid arthritis is carpal tunnel syndrome. Other neurologic manifestations of rheumatoid arthritis include headaches, compressive mononeuropathies, distal sensorimotor polyneuropathy, mononeuritis multiplex, Brown syndrome (dysfunction of the superior oblique tendon sheath complex, which could be congenital or acquired, in which case rheumatoid arthritis is one of the causes), and rarely ischemic stroke.

Question 29

Polyarteritis nodosa (PAN)

Answer 29

The patient described in this question has a history consistent with polyarteritis nodosa (PAN).

Polyarteritis nodosa leads to a vasculopathy in multiple organ systems. It presents with prominent constitutional symptoms, renal, cardiac, and gastrointestinal involvement, and may be associated with chronic hepatitis B infection. Skin manifestations include livedo reticularis, skin ulcerations, and subcutaneous nodules. Abdominal angiogram characteristically demonstrates small aneurysms in mesenteric arteries.

The neuropathy seen in these vasculitides is a necrotizing vasculitic ischemic neuropathy due to involvement of vasa vasorum. Nerve biopsy demonstrates perivascular neutrophilic inflammatory infiltrate with necrosis. Arteritis of cerebral blood vessels may also lead to ischemic stroke.

Kawasaki disease is a disorder of childhood and is characterized by acute onset of fever, conjunctivitis, mucositis, polymorphous rash, lymphadenopathy, and other findings, including increased risk coronary artery aneurysms; neurologic involvement includes

Question 31

Churg– Strauss syndrome

Answer 31

Diagnostic criteria for Churg– Strauss syndrome include asthma, eosinophilia, and sinus and pulmonary involvement.

Question 32

Wegener granulomatosis

Answer 32

Features of Wegener granulomatosis include _glomerulonephritis, paranasal sinusitis, and pulmonary involvemen_t. The presence of granulomas on biopsy and the presence of cytoplasmic antineutrophil cytoplasmic (C-ANCA) antibody and antibodies to proteinase-3 allow for the diagnosis of Wegener granulomatosis.

Question 33

Kawasaki disease

Answer 33

Kawasaki disease is a disorder of childhood and is characterized by acute onset of fever, conjunctivitis, mucositis, polymorphous rash, lymphadenopathy, and other findings, including increased risk coronary artery aneurysms; neurologic involvement includes he occurrence of aseptic meningitis.

Question 34

Takayasu arteritis

Answer 34

This patient’s history and angiographic findings are consistent with Takayasu arteritis, or pulseless disease, a large-vessel vasculitis most common in females of Asian descent. Commonly involved vessels include the subclavian arteries, but the aorta and cerebral vessels can also be involved, leading to ischemic stroke as in the case depicted in this question. Takayasu arteritis manifests with constitutional symptoms and symptoms related to organ ischemia such as peripheral claudication. Treatment is with immunosuppression and in some cases surgical or endovascular treatment of vessel stenosis or occlusion.

Question 35

Behçet disease

Question 36

APLS

Answer 36

While several systemic diseases are associated with increased risk of thrombosis, of those listed, antiphospholipid antibody syndrome (APLS) is the most likely to cause thrombosis that may involve the CNS.

APLS and most of the so-called hereditary thrombophilias, including G20210 A prothrombin polymorphism, mutation in the methylene tetrahydrofolate reductase gene (leading to hyperhomocysteinemia), factor V Leiden, antithrombin III deficiency, and protein C and S deficiency, lead to venous thrombosis. Venous sinus thrombosis is the most common neurologic manifestation of these disorders, and could lead to venous infarction. Ischemic infarcts may also occur secondary to paradoxical emboli to the cerebral vasculature from the venous system through an intracardiac right-to-left shunt. Arterial thrombosis may also occur.

Other causes of both venous and arterial thrombosis include malignancy, heparin-induced thrombocytopenia, systemic vasculitides (discussed in questions 20 and 21) and myeloproliferative diseases (such as essential thrombocythemia, polycythemia rubra vera, and others).

APLS is a disorder of coagulation resulting from the presence of circulating antibodies against phospholipid-bound proteins such as anticardiolipin antibodies and lupus anticoagulant antibodies. In addition to venous and less commonly arterial thrombosis, other neurologic manifestations seen in APLS include chorea, headaches, and seizures.

Question 38

Sarcoidosis

Answer 38

Sarcoidosis is a granulomatous, immune-mediated disorder that may involve multiple organ systems including (but not limited to) the lungs (most commonly), skin, heart, and central and peripheral nervous system. In the United States, it is more common in African- American women. Neurologic signs or symptoms as the primary presentation are rare; less than 10% of sarcoidosis cases present with extrapulmonary involvement leading to diagnosis. The most common presentation of neurosarcoidosis is cranial neuropathy, with cranial nerve VII being the most frequently affected. Multiple cranial neuropathies may occur in some patients. Other neurologic manifestations include aseptic meningitis (as in the case presented in this question), hydrocephalus, parenchymal disease/mass lesion, myelopathy, small- and large-fiber peripheral neuropathy, and myopathy. Hypothalamic or pituitary involvement may lead to endocrinopathy.

The diagnosis of sarcoidosis is established on the basis of the history, examination, and demonstration of noncaseating granulomas on biopsy. Serum angiotensin-converting enzyme (ACE) is neither sensitive nor specific, but increased serum ACE levels are a marker of disease activity. In patients with known systemic sarcoidosis, neurosarcoidosis is diagnosed in the setting of neurologic signs or symptoms and/or findings on CSF or MRI of the brain or spine (although alternative causes, such as in CNS infections in sarcoidosis patients being treated with immunosuppressive therapy must also be considered and excluded). Diffuse leptomeningeal enhancement, often with predominance at the base of the brain, is the classic finding, although focal parenchymal enhancing brain lesions can also occur (as shown in Fig. 16.2 in the splenium of the corpus callosum) as can intramedullary or extramedullary enhancing spine lesions. Treatment is with immunosuppressive therapy including corticosteroids and, in some cases, steroid-sparing agents such as methotrexate. TNF-alpha blocking agents have also been used as well as other cytotoxic agents.

Question 39

Pheochromocytoma

Answer 39

This patient’s history is concerning for pheochromocytoma, which may present with episodes of headache, diaphoresis, and palpitations in the setting of elevated blood pressure. Pheochromocytomas are neuroendocrine tumors derived from amine precursor uptake decarboxylation (APUD) cells. Included in the group of APUD cell tumors are carcinoid tumors, paraganglioneuromas, neuroblastoma, and others. Pheochromocytomas arise from chromaffin cells and secrete catecholamines. The majority arise from the adrenal medulla, although in a minority, they arise from the sympathetic ganglia, in which case they are termed catecholamine-secreting paragangliomas. Pheochromocytomas are most commonly sporadic, although in a minority, they occur as part of other syndromes such as neurofibromatosis, von Hippel–Lindau disease, tuberous sclerosis, and Sturge–Weber syndrome (discussed in Chapter 14). They are most commonly benign but are malignant in a minority of patients. Diagnosis of pheochromocytomas may be aided by measurement of catecholamines, metanephrines, and vanillylmandelic acid (VMA) in a 24-hour urine collection; measurement of plasma-free metanephrines is the most sensitive test.

Question 40

Carcinoid syndrome

Answer 40

Carcinoid syndrome can present with episodic flushing and headache associated with other symptoms; diagnosis is made by measurement of urinary 5- hydroxyindoleacetic acid.

Question 41

Pituitary

Answer 41

The anterior pituitary, or adenohypophysis, is derived embryologically from Rathke pouch, which evaginates from the oropharyngeal membrane during fetal development. The hypothalamus modulates pituitary function, and pituitary hormones in turn modulate hypothalamic function. The pituitary derives its blood supply from the superior and inferior hypophyseal arteries, which arise from the ICA. The superior hypophyseal artery forms a capillary plexus in the hypothalamic median eminence. B_lood carrying regulatory hypothalamic hormones flows from there in the hypophyseal portal vein, through the infundibulum (or pituitary stalk) to the anterior pituitary_. Secretion of prolactin by the anterior pituitary is modulated by dopamine. Growth hormone–releasing hormone secreted by the hypothalamus regulates growth hormone release by the anterior pituitary. Thyrotropin-releasing hormone secreted by the hypothalamus modulates thyroid-stimulating hormone release, and gonadotropic-releasing hormone secreted by the hypothalamus modulates release of follicle-stimulating hormone and luteinizing hormone from the anterior pituitary. ACTH release by the anterior pituitary is modulated by corticotrophin-releasing hormone from the hypothalamus.

The posterior pituitary, or neurohypophysis, originates from an extension of the neuroectoderm of the diencephalon. Magnocellular neurons in the supraoptic and paraventricular nuclei of the hypothalamus synthesize antidiuretic hormone and oxytocin. These are then moved via axonal transport, where they are stored and released by the posterior pituitary.

The classic visual field deficit occurring with pituitary masses is a bitemporal hemianopia due to pressure on the optic chiasm.

Question 42

Diabetes insipidus

Answer 42

ADH is synthesized by the magnocellular cells in the supraoptic and paraventricular nuclei of the hypothalamus and secreted by the posterior pituitary. Synthesis and secretion of ADH is modulated by serum osmolality; increases in serum osmolality normally lead to release of ADH, which stimulates renal tubular resorption of water.

Central DI manifests clinically with thirst, polydipsia, and polyuria. It is not uncommon following neurosurgery and may be transient. Other causes of central DI include trauma, hypoxic– ischemic insult, compressive lesions in the sellar or suprasellar region, and infiltration of the hypothalamus due to granulomatous diseases such as sarcoidosis (discussed in questions 25 and 26). In some cases, the disorder is idiopathic. In patients with DI, urine osmolality is low: the urine is dilute due to inadequate resorption of water and hence excessive excretion of water in the urine.

Central DI is distinguished from nephrogenic DI, which results from inadequate renal response to ADH. In patients with central

DI, administration of desmopressin (an ADH analog) will lead to urinary concentration and therefore an increase in urine osmolality and a reduction in serum sodium concentration. In nephrogenic DI, urine osmolality does not increase in response to desmopressin. One of the causes of nephrogenic DI is lithium carbonate.

The treatment of central DI includes allowing free access to water (allowing patients to maintain adequate intake of water) and administration of desmopressin. Water restriction will worsen hypernatremia, as will hypertonic saline.

Question 43

Cerebral salt wasting

Answer 43

In the setting of subarachnoid hemorrhage, and given evidence of hypovolemia, this patient’s hyponatremia is most likely due to cerebral salt wasting. This results from excessive renal losses of sodium and is seen in patients with severe CNS dysfunction. Unlike patients with syndrome of inappropriate antidiuretic hormone secretion (SIADH) who are typically euvolemic, in cerebral salt- wasting syndrome, the patient is hypovolemic, and the treatment is with salt supplementation and intravenous isotonic (or sometimes hypertonic) fluid administration. The pathophysiology of cerebral salt-wasting syndrome is not clear, but it may in part relate to increased levels of atrial natriuretic peptide released from the cardiac atria.

SIADH may occur following head trauma, neurosurgery, SAH and with paraneoplastic ectopic antidiuretic hormone production. Several medications may also cause SIADH. Treatment of SIADH is with fluid restriction and correction of underlying causes; in severe cases, diuretics may be used. Vasopressin receptor antagonists are being investigated in the neurocritical care setting.

Question 44

Postpartum cerebral angiopathy

Answer 44

This patient’s history and imaging findings are consistent with postpartum cerebral angiopathy, a disorder along the spectrum of reversible cerebral vasoconstriction syndrome. The pathophysiology of this disorder is unclear but is related to the occurrence of multifocal vasospasm. Clinically, patients present most commonly with headache, although seizure and/or focal neurologic deficit may occur. This disorder is typically benign, responsive to calcium channel blockers and/or corticosteroids. Rarely, ischemic strokes occur. Small cortical subarachnoid hemorrhages have also been reported.

Question 45

Prothrombotic states with pregnancy

Answer 45

Pregnancy and the postpartum period are hypercoagulable states, predisposing to venous sinus thrombosis. In pregnancy, levels of several of the procoagulant factors are elevated, including fibrinogen and factors VII, VIII, IX, and X. These elevations, associated with a reduction in protein S levels, increase susceptibility to venous thrombosis. Given this patient’s family history, a hereditary thrombophilia or antiphospholipid antibody syndrome may also have contributed to her risk of thrombosis

Question 46

Preeclampsia and eclampsia

Answer 46

This patient’s history, presentation, laboratory findings, and elevated blood pressure are consistent with eclampsia. Preeclampsia is characterized by gestational hypertension and proteinuria, often associated with edema in the face and hands. Eclampsia is the occurrence of seizures in association with hypertension and edema during pregnancy or in the postpartum period. The pathophysiology may relate to impaired trophoblast invasion of the endometrium and immune-mediated and endocrinologic mechanisms. Associated symptoms may include headache, visual disturbance, and epigastric abdominal pain. Postpartum eclampsia is more commonly associated with complications including disseminated intravascular coagulation and respiratory distress. In more severe cases, ischemic stroke, intracerebral hemorrhage, and/or PRES may occur.

Management of eclampsia includes delivery (which should be the priority if the pregnancy is at or close to term) and intravenous medications such as hydralazine or labetalol for blood pressure reduction (although excessive reductions should be avoided to maintain fetal blood flow). Angiotensin-converting enzyme inhibitors should be avoided given potential effects on the fetal kidney. Intravenous magnesium sulfate should be administered for the control and prevention of seizures, and should be used in this patient. Close monitoring is necessary as magnesium toxicity may lead to maternal respiratory distress. The use of AEDs is controversial, but medications that depress the fetus, such as pentobarbital or phenobarbital, should be avoided; oral diazepam is likely to be of little utility in seizure control and may depress the fetus.

Question 47

Migraines, seizures, MS, MG and pregnancy

Answer 47

Multiple sclerosis typically improves during pregnancy. The rate of multiple sclerosis relapses decline during pregnancy but may rebound afterward.

Seizure frequency in pregnant patients with epilepsy is variable and unpredictable; approximately one-third have increased seizure frequency in pregnancy, whereas the rest have a reduction or no change in seizure frequency.

The majority of women with a history of migraine have a reduction in migraines during their pregnancy, although some women may have a worsening, and migraines can occur for the first time in pregnant women without pre-existing migraines. In the latter patients, exclusion of other causes of headache such as venous sinus thrombosis (discussed in question 32) is important.

The effects of pregnancy on myasthenia gravis are variable. Approximately one- third of women have significant worsening; improvement in the second and third trimesters occurs in others, and thought to be related to the relative immunosuppression that occurs during this period. Sudden worsening in the postpartum period may occur.

Question 47

Migraines, seizures, MS, MG and pregnancy

Answer 47

Multiple sclerosis typically improves during pregnancy. The rate of multiple sclerosis relapses decline during pregnancy but may rebound afterward.

Seizure frequency in pregnant patients with epilepsy is variable and unpredictable; approximately one-third have increased seizure frequency in pregnancy, whereas the rest have a reduction or no change in seizure frequency.

The majority of women with a history of migraine have a reduction in migraines during their pregnancy, although some women may have a worsening, and migraines can occur for the first time in pregnant women without pre-existing migraines. In the latter patients, exclusion of other causes of headache such as venous sinus thrombosis (discussed in question 32) is important.

The effects of pregnancy on myasthenia gravis are variable. Approximately one- third of women have significant worsening; improvement in the second and third trimesters occurs in others, and thought to be related to the relative immunosuppression that occurs during this period. Sudden worsening in the postpartum period may occur.

Question 48

APLS associated syndromes

Answer 48

Patients with antiphospholipid antibody syndrome may present with acute-onset chorea. This is known as chorea gravidarum. It was previously associated most often with rheumatic fever, but with the decline in incidence of rheumatic fever in recent decades, other causes such as antiphospholipid antibody syndrome have emerged as being more common and should be checked for.

In the third case depicted in this question, a young woman with a family history of Huntington disease wishes to be tested prior to pregnancy. Referral to a genetic counselor and genetic testing is appropriate.

In the fourth case, assessment for hyperthyroidism is indicated in the setting of new-onset tremor during pregnancy. Thyroid stimulating hormone should be checked.

The fifth case depicts a patient with fever and rigidity following initiation of an antipsychotic, a story that may be consistent with neuroleptic malignant syndrome. The diagnosis is a clinical one, although measurement of serum creatine kinase level is indicated as it is often elevated. Checking serum copper and ceruloplasmin levels, tests for Wilson disease (discussed in Chapter 6), may be indicated as part of the initial workup of this patient’s underlying neuropsychiatric illness but would not be the first line of testing for this acute presentation.