13

Systemic Diseases Affecting

the Nervous System

Note: Significant diseases are indicated in bold and syndromes in italics.

I. Diabetes Mellitus (DM)

1.Subtypes

a.type I/insulin-dependent DM: caused by autoimmune destruction of islet cells of the pancreas leading to insulin deficiency

i.common antibodies include those against insulin and glutamate decarboxylase (Box 13.1)

ii.typical patient is 45 years of age, thin, and prone to ketosis; frequently associated with other autoimmune diseases

b.type 2/noninsulin-dependent DM: caused by peripheral tissue insulin resistance; not associated with autoimmune diseases

i.typical patient is 30 years of age, obese, and ketosis-resistant

c.secondary diabetes: from glucocorticoid administration, Cushing’s syndrome, acromegaly, or pheochromocytoma

2.Diabetic neuropathies: identification of diabetic neuropathy is complicated by the association of DM with other neuromuscular diseases (ataxia telangiectasia, Friedreich’s ataxia, myotonic dystrophy, amyloidosis, porphyria, glycogen storage diseases, mitochondrial myopathies, and stiff man’s syndrome)

a.subtypes

i.symmetric diabetic neuropathies

(1)diabetic chronic sensorimotor neuropathy—most common form of DM neuropathy (30% of all DM neuropathy)

(a)pathophysiology: glucose is converted to sorbitol by aldose reductase and sorbitol dehydrogenase, and the accumulation of intracellular sorbitol causes cellular edema that injures primarily the vasculature and the Schwann cells

(i)histology: microvascular thickening with hyalinization, and axonal degeneration of large and small fibers; complement deposition occurs in the microvasculature with inflammatory infiltrates

(ii)risk factors include obesity, diastolic hypertension, dyslipidemia, inadequate glucose control, and other end-organ damage (albuminuria, retinopathy)

(b)symptoms

(i)distal pain and paresthesias

(ii)distal sensory loss leading to foot ulcerations and neuropathic osteoarthropathy (Charcot’s joints)

(iii)mild weakness; areflexia

(iv)may have some dysautonomia

(2)diabetic autonomic neuropathy

(a)pathophysiology: degeneration of CN X and other autonomic nerves

Box 13.1

Antibodies against glutamate decarboxylase also occur in stiff man’s syndrome.

Diabetes Mellitus (DM)

293

(i) 10-year risk 5%, for clinical manifestations, 30% for subclinical manifestations; more common in type I DM

Box 13.2

Multiple mononeuropathies can give the appearance of a mononeuritis multiplex.

Table 13–1 Diabetic and Hypoglycemic Comas

Abbreviations: GI, gastrointestinal; IV, intravenously; PO, orally.

i.risk factors include inadequate glucose control, other end organ damage (retinopathy, nephropathy, neuropathy), and hypertension

ii.epidemiology: more common in women and type I diabetics

b.symptoms: acute pain, tenderness, and swelling of the muscle, which is exacerbated by movement; usually located in the anterior or medial thigh calf

c.diagnostic testing

i.normal or elevated CK

ii.elevated erythrocyte sedimentation rate (ESR), usually 100

iii.plain films can demonstrate vascular mineralization

iv.MRI: demonstrates edema in muscle and perifascial space with fluid collection in tissue planes; minimal contrast enhancement

v.muscle biopsy shows necrotic muscle fibers, hyaline thickening of the arterioles, and perivascular inflammation

d.treatment: rest; analgesics; gradual mobilization

e.prognosis: spontaneous resolution over weeks to months; recurs in 60%, but not necessarily in the same muscle group

4.Diabetic and hypoglycemic comas (Table 13–1)

Hypertension

Box 13.3

Other causes of posterior reversible leukoencephalopathy—immunosuppressant medications; HIV/AIDS; post-carotid endarterectomy reperfusion; thrombotic thrombocytopenic purpura

Autoimmune Disorders

297

Box 13.5

Stroke is particularly common with antiphospholipid antibody syndrome (see p. 73).

Box 13.6

Heerfordt syndrome

Sarcoid presenting as uveitis, salivary gland inflammation, and multiple cranial nerve palsies

(c)focal spinal cord injury resembling transverse myelitis

(d)mild personality changes

iii.myopathy, but never involving the ocular motor muscles c. diagnostic testing for neurological disease

i.neuroimaging may demonstrate granulomas

ii.cerebrospinal fluid analysis demonstrates lymphocytic pleocytosis, increased angiotensin-converting enzyme (40%), increased protein (70%), and/or decreased glucose (20%) levels

(1)may exhibit oligoclonal bands like multiple sclerosis

iii.muscle and nerve biopsy demonstrates granulomas in mononeuropathies or vasculitis in symmetric polyneuropathies

d.treatment

i.brain involvement: glucocorticoids

ii.peripheral neuropathy: glucocorticoids; immunosuppressants

e.prognosis: 10% mortality in cases with neurological involvement

5.Sjögren’s syndrome

a.pathophysiology: autoimmune destruction of the lacrimal and salivary glands involving T lymphocyte and plasma cell infiltration; affected peripheral nerves also demonstrate perivascular lymphocyte infiltration

b.symptoms

i.dry eyes and mouth {sicca syndrome}

ii.large and small fiber sensory neuropathy (20%), which may precede the sicca syndrome; may present as a polyradiculoneuropathy with pronounced large fiber sensory deficits causing ataxia

c.treatment: neuropathy is generally resistant to glucocorticoids

6.Antiphospholipid antibody syndrome (see p. 73)

Nutritional Disorders

V. Nutritional Disorders

1.Celiac disease/gluten-sensitive enteropathy

a.pathophysiology: caused by an immune reaction against gluten proteins (e.g., gliadin)

b.symptoms

i.general symptoms: episodic malabsorption

ii.neurological symptoms (10%): progressive ataxia (Box 13.7) and cerebellar dysarthria, and myoclonus; rarely associated with neuropathy, myelopathy, and/or dementia

c.diagnostic testing for neurological disease

i.serum antigliadin antibodies, and IgA antibodies against smooth muscle endomysium

ii.neuroimaging demonstrates atrophy of the cerebellum and cerebral cortex with white matter lesions and calcifications

d.treatment: gluten-free diet; (oats are the only safe grain)

2.Vitamin B1/thiamine deficiency

a.biochemical actions: thiamine is a cofactor in the conversion of pyruvate to -ketoglutarate in TCA cycle (pyruvate decarboxylase) and in the pentose phosphate shunt (transketolase)

b.thiamine deficiency is caused by malnutrition

c.symptoms: become pronounced during glucose administration

i.beriberi

(1)general symptoms: cardiomyopathy; muscle cramps

(2)neurological symptoms: sensorimotor polyneuropathy; optic neuropathy

Box 13.7

Celiac disease may account for 40% of sporadic idiopathic ataxias.

299

13 Systemic Diseases Affecting the Nervous System

ii.Wernicke’s encephalopathy—symptoms include

(1)ataxia with minimal limb dysmetria

(2)nystagmus: horizontal vertical

(3)ophthalmoplegia: horizontal paralysis other directions; light-near dissociation

(4)encephalopathy, but coma is rare

(5)autonomic instability

iii.Korsakoff’s syndrome—always develops from a Wernicke’s encephalopathy; symptoms include anterograde and retrograde amnesia, confabulation, and residua from Wernicke’s encephalopathy (lateral nystagmus, ataxia)

3.Vitamin B6/pyridoxine deficiency (Box 13.8)

a.biochemical action: vitamin B6 is a necessary cofactor of several enzymes involved in amino acid metabolism

b.causes of vitamin B6 deficiency

i.neonates: breastfeeding from malnourished mothers

ii.adults: hydralazine, isoniazid, or penicillamine use

c.symptoms

i.neonates: irritability with excessive auditory startle; medicationresistant seizures

ii.adults: painful sensorimotor neuropathy

4.Vitamin B12 deficiency

a.biochemical actions: vitamin B12 is a cofactor in the conversion of homocysteine to methionine (cystathionine -synthase) and the conversion of methylmalonyl CoA to succinyl CoA (methylmalonyl-CoA mutase; see p. 73)

b.causes of vitamin B12 deficiency include

i.intrinsic factor deficiency due to parietal cell destruction in the stomach

ii.ileum resection leading to malabsorption of the vitamin

iii.HIV/AIDS

iv.nitrous oxide intoxication

c.symptoms: anemia and neurological symptoms are not necessarily correlated

i.general symptoms: pernicious/megaloblastic anemia, which may be masked by folate supplementation

ii.neurological symptoms: not affected by folate supplementation

(1)myelopathy/subacute combined degeneration—symptoms include

(a)distal paresthesias and pain

(b)spastic weakness in the lower upper extremities due to corticospinal tract degeneration; reflexes may be diminished, not increased, due to a coincident peripheral neuropathy

(c)ataxia from degeneration of the spinocerebellar tracts

(d)loss of vibratory and position sense in the lower upper extremities that often extend onto the trunk, from degeneration of the dorsal columns; may give the false appearance of a sensory level

(2)large fiber sensory neuropathy

Box 13.8

Vitamin B6 overdose can cause peripheral neuropathy.

Table 13–3 Other Vitamin Deficiencies

Abbreviations: NAD, nicotinamide adenine dinucleotide; NADP, nicotinamide adenine dinucleotide phosphate.

(3)encephalopathy involving depression and psychosis that may progress to coma

(4)dementia

(5)optic neuropathy with atrophy

iii.spina bifida in cases of prenatal deficiency

5.Other vitamin deficiencies (Table 13–3)

Appendix 13–1 Electrolyte Abnormalities Relevant to the Nervous System

Nutritional Disorders