Systemic disease

Endocrine Diseases• Diabetes MellitusDM is a systemic metabolic disorder

characterized by hypoinsulinism or peripheral resistance to the action of insulin.

the presence of neurologic disease is roughly correlated with the duration and severity of the disease and is commonly associated with other tissue complications of DM, such as retinopathy and nephropathy.

• The primary neurologic complication of DM is peripheral neuropathy.

• This includes mononeuropathies (peripheral and cranial nerves), polyneuropathy, autonomic neuropathy, radiculopathies, and entrapment neuropathy (median, ulnar, and peroneal;).

• Mononeuropathies are attributed to vascular lesions of peripheral nerves.

Onset of symptoms is rapid, and pain is common in both mononeuropathies and radiculopathies caused by DM. Common cranial neuropathies involve the oculomotor and abducens nerves and are also a result of vascular lesions. Pupillary sparing is common.

The prognosis for recovery from mononeuropathy or radiculopathy is good.

• Distal symmetric polyneuropathy of DM is the one most commonly encountered.

There is typically a gradual onset of symptoms. Numbness and burning are common complaints.

Distal sensory loss may be accompanied by weakness; tendon reflexes are usually lost.

Diagnosis of diabetic polyneuropathy is aided by nerve conduction studies .

Autonomic neuropathy may be prominent in DM. Cardiovascular symptoms include arrhythmias or

orthostatic hypotension.

Gastrointestinal motility problems can produce nausea, vomiting, or diarrhea, depending on the severity and distribution of the autonomic neuropathy.

Diabetic neuropathy may lead to bladder dysfunction or erectile and ejaculatory failure in men.

• CNS complications of DM are primarily owing to the metabolic derangements of hypoinsulinism and hypoglycemia.

• Cerebrovascular disease is an important problem in diabetics because of accelerated atherosclerosis of cerebral blood vessels and related cardiovascular disorders of heart failure, hypertension, and coagulation abnormalities.

• HypoglycemiaThe CNS depends almost entirely on glucose for its

metabolism; dysfunction develops rapidly when the amount of glucose in the blood falls below critical levels.

Hypoglycemic symptoms can be divided into two groups: autonomic and cerebral. Sympathetic symptoms are present in most patients at the onset of hypoglycemia.

Autonomic symptoms include lightheadedness, sweating, nausea, vomiting, pallor, palpitations, headache, abdominal pain, and hunger. In DM with autonomic failure, many of these symptoms may not occur.

• Cerebral symptoms : The most common manifestations are paresthesias,

diplopia, and blurred vision, which may be followed by tremor, focal neurologic abnormalities, abnormal behavior, or convulsions.

After prolonged, severe hypoglycemia, coma may ensue.

Confusion and abnormal behavior from episodic hypoglycemia may simulate complex partial seizures

. Chronic or repeated hypoglycemia may produce dementia or other behavioral abnormalities. Distal axonal neuropathy has also been observed.

• HypothyroidismThyroid hormone is important in early growth and

development, and the neurologic consequences of hypothyroidism depend on the age of the patient when the deficiency begins.

Severe thyroid deficiency in utero or early life results in delayed physical and mental development, or cretinism.

Neurologically, there is MR, with pyramidal and extrapyramidal signs. Strabismus, deafness, and primitive reflexes are common.

Juvenile myxedema is similar to cretinism. The severity of physical and mental retardation is usually less than in infantile myxedema.

Adult myxedema is characterized by lethargy, somnolence, or impairment of attention and concentration; weakness; slowness of speech.

The neurologic complications of hypothyroidism include headache, disorders of the cranial and peripheral nerves, sensorimotor abnormalities, and changes in cognition and level of consciousness.

Cranial nerve abnormalities, other than visual and acoustic nerve problems, are unusual.

Hearing loss, vertigo, and tinnitus may be present. The cause of headache is uncertain. Pseudotumor cerebri has been reported in

hypothyroidism in children receiving thyroid replacement therapy.

A mild, primarily sensory neuropathy is characterized mainly by paresthesias in the hands and feet.

Entrapment neuropathy of the median nerve (CTS) is attributed to the accumulation of acid mucopolysaccharides .

Neuromuscular findings include slowing of voluntary movements and slow relaxation of tendon reflexes, particularly the ankle jerks.

There may be exercise intolerance or myopathic weakness. Serum creatine kinase levels are elevated.

Cerebellar ataxia may occur in adults, manifesting as incoordination with a slow or stiff, unstable gait.

Mental status changes may be prominent, with decreased attentiveness, poor concentration, lethargy, and dementia.

Myxedema coma may be accompanied by hypothermia, hypotension, and respiratory and metabolic disturbances, and, if untreated, has a high mortality rate.

The characteristic findings are low circulating T4 and T3, elevated TSH, and low radioiodine uptake by the thyroid. The CSF protein content increases; values greater than 100 mg/mL are not exceptional.

• HyperthyroidismHyperthyroidism or thyrotoxicosis is associated

with an increased metabolic rate, abnormal cardiovascular and autonomic functions, tremor, and nervousness.

It may present with minimal clinical signs or as AF with stroke in older adults.

Mental disturbances range from mild irritability to psychosis.

When hyperthyroidism is associated with diffuse goiter, ophthalmopathy, and dermopathy, it is termed Graves disease, which is an autoimmune disorder.

Onset of symptoms is gradual; exophthalmos is often accompanied by diplopia secondary to paresis of one or more ocular muscles.

Clinically, eyelid retraction is the first evidence in 75% of cases, and pain is the most common symptom.

Both eyes may be involved simultaneously, or exophthalmos in one eye may precede the other by several months.

Papilledema sometimes occurs. The symptoms progress rapidly for a few months and

may lead to complete ophthalmoplegia. As a rule, the symptoms persist unchanged throughout a

patient's life unless relieved by therapy.

• Hashimoto encephalopathy, is a brain disorder in a patient with antithyroid antibodies.

• Antithyroid antibodies form in the autoimmune condition of Hashimoto thyroiditis. This thyroid disease is characterized by goiter and varying degrees of thyroid dysfunction.

• Patients may have discrete episodes of stroke-like events or develop a progressive decline with dementia and psychiatric symptoms.

• Additional manifestations found in a review of the literature are tremor, seizures, or myoclonus.

• Limb weakness is common with hyperthyroidism.

• Thyrotoxic myopathy is characterized by painless weakness and wasting of the muscles of the pelvic girdle, to a lesser extent, the muscles of the shoulder girdle.

• Tendon reflexes are normal or hyperactive, and sensation is normal.

• Fasciculations or myokymia may be noted. Thyrotoxic myopathy needs to be distinguished from myasthenia gravis (MG), which may accompany hyperthyroidism.

• The occurrence of hyperthyroidism and periodic paralysis is more common in people of Asian, predominantly men.

• There is an association between hyperthyroidism and MG. About 5% of patients with MG have hyperthyroidism.

• If there are cranial symptoms (dysarthria, dysphagia, ptosis) in a hyperthyroid patient, MG should be suspected.

• Hypoparathyroidismclinical features of hypoparathyroidism and

pseudohypoparathyroidism include mental deficiency, cataracts, tetany, and seizures .

Other neurologic manifestations are directly related to the effects of hypocalcemia on the nervous system.

Dementia and psychosis occur with variable improvement after correction of hypocalcemia. Convulsions are a symptom of hypocalcemia regardless of cause.

Although rare, hypoparathyroidism should be considered when seizures are frequent or bizarre and difficult to control with medication.

• Intracranial calcifications are common in hypoparathyroidism.

• The basal ganglia are the predominant site for calcium deposition. The calcifications are usually not associated with symptoms, but cognitive impairment and a variety of hypokinetic and hyperkinetic movement disorders have been reported.

• Increased ICP with papilledema has been reported with hypoparathyroidism. The mechanism is unexplained.

• HyperparathyroidismCommon symptoms include fatigue and

subjective weakness. Mental status changes include memory loss,

irritability, and depression. Neuromuscular signs include symmetric

proximal limb weakness and muscle wasting. EMG and muscle biopsy may show evidence of

myopathic or neuropathic disease. These signs and symptoms typically respond to parathyroidectomy.

• HypoadrenalismHeadaches are common even in the absence of

increased ICP. Idiopathic intracranial hypertension has been

described with Addison disease, as well as with steroid withdrawal in hypercortisolism.

Muscle cramps and stiffness may occur with adrenal insufficiency, but overt proximal weakness is uncommon.

• CNS manifestations of Addison disease are common, primarily in cognition and behavior. Patients with adrenal failure are frequently fatigued or apathetic.

• HyperadrenalismMental status changes, including difficulties with memory,

and myopathy are two of the more common neurologic symptoms.

The syndrome of idiopathic intracranial hypertension with headache, nausea, vomiting, and papilledema may occur with reduction or withdrawal of corticosteroids being used as therapy.

• PheochromocytomaHypertension of a moderate or severe degree is

characteristic. The hypertension is associated with palpitations, episodic

hyperhidrosis, headaches, and other nonspecific systemic symptoms, such as nausea, emesis, or diarrhea. Anxiety attacks are common.

• PITUITARYHeadache and visual loss are common when tumors are

large(>10 mm) and extend into the suprasellar region in the vicinity of the optic chiasm.

Lateral extension of masses may produce syndromes involving structures in the cavernous sinus.

Growth of tumors superiorly may compress the hypothalamus and obstruct the CSF pathways to cause hydrocephalus.

Vascular lesions of the pituitary may cause dramatic and life-threatening onset of hypopituitarism.

In pituitary apoplexy, sudden hemorrhage into a pituitary tumor may cause headache, meningismus, visual loss, oculomotor abnormalities, and alteration in the level of consciousness.

• GH-secreting pituitary tumors are the most common cause of acromegaly .

Patients complain of headaches, fatigue, muscular pain, visual disturbances. Paresthesias, sometimes with a typical CTS, may be present.

Hematologic and Related Diseases• Sickle Cell Disease

Sickled red cells tend to adhere to the vessel wall, resulting in vaso-occlusive disorders in kidney, bone, lung, liver, heart, spleen, peripheral nerves, and brain.

Neurologic complications include ischemic stroke, intracranial hemorrhage, seizures, CNS infections, retinopathy, myelopathy, sensorineural hearing loss, and neuropathy.

Cerebral infarcts appear at a mean age of 8 years.Cerebral infarcts are due to either large- or small-vessel

disease. The mechanisms of infarction include occlusion or stenosis of

large intracranial arteries (most commonly the ICA and MCAs).

Hemorrhage accounts for one-third of all strokes in sickle cell disease.

SAH is more common in children, while intraparenchymal hemorrhage occurs more often in adults.

Epilepsy is more common in sickle cell patients than in the general population, affecting 6% to 12% of patients.

Myelopathy is rare but may follow spinal cord infarction or cord compression from epidural abscess or tumorlike extramedullary hematopoiesis. Sensorineural hearing loss is attributed to cochlear ischemia.

• β-ThalassemiaHeadaches and seizures are seen in 13% of

patients. 20% develop a mild peripheral, mainly motor, neuropathy in the second decade of life. Stroke is a rare complication.

Intracranial hemorrhage and cerebral thrombosis have been reported presumably due to coagulopathy from liver dysfunction, cardiac abnormalities such as AF and ventricular dysfunction, and thrombocytosis from splenectomy.

• PolycythemiaPolycythemia causes hyperviscosity of the blood,

leading to accelerated atherosclerosis and thrombosis in both large and small vessels.

In polycythemia vera, TIAs and ischemic strokes account for 70% of arterial thrombotic events. Cerebral venous thrombosis is rare.

Essential ThrombocytosisNeurologic manifestations occur in 30% of patients ,

including headache, paresthesias, TIA, and seizures.

Bleeding complications are seen paradoxically at very high platelet counts (1,500,000/µL).

• Thrombotic Thrombocytopenic Purpura TTP is characterized by thrombocytopenia,

microangiopathic hemolytic anemia, fever, renal abnormalities, and neurologic manifestations.

Fluctuating neurologic symptoms, usually lasting less than 48 hours, occur in 70% of patients. Headache, confusion, and stupor are the most common and lead to focal neurologic signs, seizures, coma, or death.

The fluctuating stupor of TTP has been ascribed to microvascular occlusive disease , but nonconvulsive status epilepticus may occur, and EEG monitoring should be considered.

• LeukemiaDirect CNS manifestations of leukemia depend on

the specific cell type involved.Leukostasis may occlude cerebral blood vessels.

Furthermore, leukemic blasts can infiltrate the arteriole endothelial walls to cause hemorrhage.

With leptomeningeal seeding, the CSF cytology is invariably abnormal. As with carcinomatous meningeal involvement, all levels of the CNS are affected, with cranial nerve signs (III, IV, VI, and VII), seizures, cognitive deficit, or hydrocephalus.

• Plasma Cell DyscrasiasPeripheral neuropathy is a common neurologic

manifestation of MGUS(monoclonal gammopathy of unknown

significance) . In most cases, the paraprotein is IgM .In about half of the patients with IgM neuropathy, the

monoclonal protein has antibody activity against myelin-associated glycoprotein (MAG) and results in a demyelinating peripheral neuropathy.

In myeloma, the protein is usually IgG. The most frequent neurologic complication is thoracic

or lumbosacral radiculopathy, resulting from nerve compression by a vertebral lesion or collapsed bone.

Leptomeningeal invasion is also seen with myeloma.

• COAGULATION DISORDERSMost prothrombotic disorders are associated with

venous thrombosis in unusual sites (mesentery, sagittal sinus), but arterial thrombosis, mainly in the carotid artery, has been described.

AT deficiency :The most common manifestation is leg thrombosis and pulmonary embolus. In heterozygotic individuals, symptomatic thrombosis increases after the age of 15.

More than half of the thrombotic episodes occur with triggering events: pregnancy, surgery, infection, or OCP use.

Cerebral venous thrombosis is the most common neurologic manifestation. Arterial thrombosis may occur, but is not characteristic of AT deficiency.

Protein S Deficiency:The complex of proteins C and S inhibits the clotting cascade.

Acquired deficiency is caused by pregnancy, oral contraceptives, liver dysfunction, vitamin K deficiency, warfarin therapy, nephrotic syndrome, HIV infection.

Thrombosis may affect either arteries or veins.Protein C Deficiency:Cerebral venous

thrombosis has been linked to inherited protein C deficiency, usually with a second risk factor such as oral contraceptives or smoking.

strokes are usually attributed to venous thrombosis. Acquired protein C deficiency may occur with liver disease, vitamin K malabsorption or warfarin therapy, infections and sepsis, DIC, or with malignancy or chemotherapy.

• Factor V Leiden and Prothrombin G20210A Mutations

Factor V Leiden is the most common known genetic risk factor for thrombosis.

Deep venous thrombosis is the most common clinical manifestation. Cerebral vein thrombosis occurs with increased frequency in heterozygotes.

• Antiphospholipid antibodies, encompassing the lupus anticoagulant and anticardiolipin antibodies, are the most common acquired defects associated with thrombosis.

Other manifestations of the antiphospholipid antibody syndrome include fetal loss, thrombocytopenia, and livedo reticularis. Recurrent events are common.

Other neurologic manifestations of antiphospholipid antibodies include cerebral venous sinus thrombosis, dementia, and chorea.

• Hemophilia 25% percent of hemorrhagic deaths in

hemophilia are a result of intracranial bleeding.

Bleeding may be subdural, epidural, intracerebral, or intraspinal.

Hepatic DiseaseAlteration in mental status as a result of acute, subacute,

or chronic liver failure is hepatic encephalopathy.coma is usually a single event of rapid onset and

fulminant course that is characterized by delirium, convulsions, and, occasionally, decerebrate rigidity.

The clinical syndrome resulting from shunting(portal-systemic ) is an episodic encephalopathy comprising admixtures of ataxia, action tremor, dysarthria, confusion, and asterixis.

The irreversible disorder has been termed acquired chronic hepatocerebral degeneration.

Mental dullness and drowsiness are usually the first symptoms.

Cognitive defects eventually appear. Asterixis almost always accompanies these

modest changes of consciousness.bilateral Babinski signs are usually found when

obtundation becomes profound. Decerebrate and decorticate postures and

diffuse spasticity of the limbs frequently accompany deeper stages of coma.

Renal Disease• CNS COMPLICATIONS OF RENAL FAILUREUremic EncephalopathySensorial clouding, which progresses to delirium, and even

coma. Focal symptoms and signs including weakness and

dysarthria may wrongly suggest a focal structural lesion. Fluctuation of clinical symptoms and signs from day to day

is characteristic. Asterixis is a dramatic problem. Multifocal myoclonus, may become apparent. Seizures are a late manifestation of uremic

encephalopathy.

• Dialysis Disequilibrium Syndrome Dialysis disequilibrium syndrome is usually seen with rapid

dialysis at the start of a dialysis program. Symptoms vary from mild headache, nausea, and muscle

cramps to, rarely, obtundation, convulsions, or delirium. The syndrome is usually self-limited.

• Cerebrovascular Disease • Stroke is prevalent in patients with renal failure, mostly

because of shared risk factors.• However, renal failure may additionally promote

atherogenesis through several mechanisms. Hypotension during dialysis may result in watershed infarction.

• Renal failure is associated with platelet dysfunction, and anticoagulants used during hemodialysis may contribute to ICH or SDH.

• Benign Intracranial Hypertension Benign intracranial hypertension or pseudotumor

cerebri is thought to occur more frequently in patients with chronic renal failure.

• Peripheral NeuropathyThe most common neurologic consequence of

CRF is a distal, symmetric, predominantly axonal, mixed sensorimotor neuropathy affecting the legs more than the arms.

Cranial nerves, particularly vision and hearing, and the autonomic nervous system may be affected.

• Mononeuropathies, such as carpal tunnel syndrome caused by damage to the median nerve at the wrist or ulnar neuropathy, may occur.

• Myopathy In patients with renal failure, myopathy, with

proximal limb weakness, fatigability, and atrophy is a poorly understood condition. Muscle enzymes and EMG are usually normal.

Nutritional Disorders

• VITAMIN B12 (COBALAMIN) DEFICIENCY

About 40% of all patients with B12 deficiency are said to have some neurologic symptoms or signs.

Usually, there are features of both myelopathy and peripheral neuropathy.

The most common symptom is acroparesthesia, burning and painful sensations that affect the hands and feet.

There may be sensory ataxia. Memory loss, visual loss (owing to optic neuropathy).

• there is glove-stocking sensory loss, and almost all patients show loss of vibratory sensation and of position sense.

• The Romberg sign is often present.• There may or may not be weakness of limb

muscles;• the neuropathy is predominantly sensory, but

there are upper motor neuron signs: increased tone, impaired alternating movements, and hyperactive tendon jerks, with Babinski and Hoffmann signs.

• Cognitive loss may be evident as florid dementia or may be manifest only on neuropsychologic tests.

• Thiamine deficiency neuropathy

• The classic triad of Wernicke's encephalopathy (WE) includes(Thiamine deficiency ):

Encephalopathy,Oculomotor dysfunction,Gait ataxia

Vasculitis

• periarteritis nodosaPeripheral neuropathy; mononeuritis multiplex;

stroke; polymyositis• Wegener granulomatosisPeripheral or cranial neuropathy, encephalopathy• Temporal arteritis (giant cell arteritis)Visual loss due to lesions of optic nerve or retina;

papilledema; stroke rare

• Takayasu syndrome (aortic arch disease)Stroke; amaurosis fugax; visual loss• Granulomatous angiitis of the brainSomnolence, confusion; encephalomyelopathy;

myeloradiculoneuropathy ,clinical manifestations are restricted to the brain.

• Systemic lupus erythematosusOrganic psychosis; seizures; chorea; myelopathy;

peripheral neuropathy; polymyositis; aseptic meningitis, Stroke, TIA, Optic neuropathy.

These symptoms are often attributed to thrombosis of small vessels or petechial hemorrhages.

• Rheumatoid arthritisPolymyositis; mononeuritis multiplex peripheral

neuropathy• Systemic sclerosisPolymyositis• Behçet SyndromeAn inflammatory disorder of unknown cause,

characterized by the occurrence of relapsing uveitis and recurrent genital and oral ulcers.

Any portion of the nervous system may be affected. Cranial nerve palsies are common.

• Other symptoms and signs include papilledema, convulsions, mental confusion, coma, aphasia, hemiparesis, quadriparesis, pseudobulbar palsy, and evidence of involvement of the basal ganglia, cerebellum, or spinal cord.

• The diagnosis is based on the occurrence of signs of meningoencephalitis in combination with the characteristic cutaneous and ocular lesions.

• The disease may simulate MS with multifocal involvement of the nervous system, including the brain stem, cerebellum, and corticospinal tract.

Paraneoplastic Syndromes• Neurologic paraneoplastic disorders are caused by

indirect damage to central or peripheral nervous system structures from a systemic cancer.

• The neurologic disorder is not the result of tumor invasion or metastasis, toxicity from chemotherapy or radiotherapy, malnutrition, or coincidental infection.

• Most paraneoplastic disorders are probably immune-mediated, marked by the frequent presence of characteristic antibodies against neuronal antigens.

• Paraneoplastic Cerebellar DegenerationAtaxia of gait and limbs, dysarthria, nystagmus,

and oscillopsia.Associated antibodies may be anti-Yo with

gynecologic cancers, anti-Hu with small cell lung cancer, anti-Tr or anti-GluR1 with Hodgkin disease, or anti-Ri with breast cancer.

• Sensory NeuronopathyThis syndrome is usually accompanied by anti-

Hu antibody, usually with small cell lung cancer.

• Limbic EncephalitisPersonality and mood changes progress rapidly,

and within weeks the syndrome is dominated by delirium and dementia with severe memory loss.

The anti-Ma2 antibody ,with testicular cancer, anti-Hu antibody in patients with small cell lung cancer.

• Brain Stem Encephalitis Symptoms of brain stem encephalitis are usually

part of a more widespread encephalomyelitis in the anti-Hu syndrome.

• Sensorimotor Peripheral NeuropathyAnti-MAG paraproteinemic peripheral neuropathy

associated withWaldenström macroglobulinemia, and paraneoplastic neuropathy.

• Neuromuscular Disorders The association of MG with thymoma. 60% of LEMS( Lambert-Eaton myasthenic) syndrome

cases occur with small cell carcinoma of the lung. • Myopathies About 20% of patients with dermatomyositis starting

after age 40 have an associated tumor, which can be of almost any type.

Neurosarcoidosis• Sarcoidosis is a multisystem, granulomatous

disease of unknown cause.• Although any cranial nerve may be affected,

the most frequently affected is the seventh.• Facial weakness may be bilateral .• Optic nerve involvement causes papillitis or

retrobulbar neuritis and eventually optic atrophy.Granulomas involve the hypothalamus more often than the pituitary.

• Cerebral granulomas may be scattered diffusely. Seizures are common in such patients.

• Rarely, sarcoid vasculitis causes cerebral infarction .• Intraparenchymal or extraparenchymal spinal cord

lesions can cause back pain and spastic paraparesis.• Meningeal infiltration may be asymptomatic or may

produce symptomatic aseptic meningitis.• Peripheral nerve lesions cause mononeuropathy,

mononeuropathy multiplex, and polyneuropathy, either chronically progressive or resembling Guillain-Barré neuropathy.