Hepatitis B

Approximately one-third of cases of polyarteritis nodosa are associated with hepatitis B infection. More than 80 percent of patients with hepatitis B–associated polyarteritis nodosa have a neuropathy. Although the clinical features may be indistinguishable from classic polyarteritis nodosa, the disease manifestations of hepatitis B–associated vasculitis may be more severe. Immune complex deposition is thought to be the main immunopathologic mechanism.

Treatment of hepatitis B–related vasculitic neuropathy is specialized. Although immunosuppressive therapies lead to increased viral replication, two retrospective studies suggest that a short course of corticosteroids is beneficial. Following the steroid therapy, either interferon-α or lamivudine may be used for at least 6 months. Plasma exchanges are usually given concurrently over a 10-week period to clear the immune complexes. Relapses are uncommon.

Hepatitis C

A minority of patients with hepatitis C virus (HCV) infection develop a peripheral neuropathy, sometimes associated with cryoglobulinemia. As cryoglobulinemia can cause a vasculitic neuropathy with more severe neurologic deficits, the following discussion focuses on it.

HCV is the most common cause of essential mixed cryoglobulinemia, which occurs in about one-third of patients with HCV; a cryoglobulinemic neuropathy only occurs in 2 to 3 percent of patients. Other manifestations of cryoglobulinemia include edema, palpable purpura, and membranoproliferative glomerulonephritis. The cryoglobulinemia results from an oligoclonal expansion of B-lymphocytes. Most cryoglobulinemic neuropathies are distal, axonal, and symmetric with predominantly sensory deficits. Mononeuropathies, either single or multiple, may also occur. Rarely, patients with cryoglobulinemia may develop demyelinating polyneuropathies associated with IgM binding to myelin.

The best treatment strategy for HCV-associated cryoglobulinemic neuropathy is not known but mild neuropathies are often treated with pegylated interferon-α2b (INF-α) plus ribavirin. The INF-α may occasionally exacerbate a vasculitic neuropathy or produce a new multifocal neuropathy. For severe neuropathies refractory to INF-α, immunosuppression with corticosteroids combined with cyclophosphamide or plasmapheresis should be considered. Another treatment option for patients refractory to INF-α is administration of monoclonal anti-CD20 antibodies (rituximab).

Other Infections

Any organism can produce a vasculitis if it elicits either circulating or in situ immune complexes. CMV and herpes zoster are the only two infections known to infect endothelial cells of peripheral nerve blood vessels.

HIV infection ( Chapter 44 ) may rarely cause a systemic vasculitis. It usually occurs in the early symptomatic stage of the disease. Multiple patterns of nerve involvement have been described, including mononeuropathy, mononeuritis multiplex, cranial neuropathies, distal symmetric polyneuropathy, and asymmetric polyneuropathy. The possibility of CMV vasculitis must be excluded in this patient population. In CMV-negative cases, nerve biopsy samples show a necrotizing vasculitis that may involve the endoneurial vessels in addition to the epineurial vessels. Other causes of multifocal neuropathies in HIV patients include neurolymphomatosis and diffuse infiltrative lymphocytosis syndrome.

Diabetic Polyneuropathy

As discussed in Chapter 19 , diabetes mellitus may be associated with both generalized and focal neuropathies. The focal neuropathies include lumbosacral radiculoplexus neuropathy (diabetic amyotrophy; proximal diabetic neuropathy), thoracolumbar neuropathy, entrapment neuropathies, and cranial neuropathies. The generalized neuropathies include distal symmetric sensory or sensorimotor polyneuropathy, acute painful neuropathy, autonomic neuropathy, and acute motor neuropathy.

Approximately 50 percent of diabetics develop a distal symmetric sensorimotor polyneuropathy. Risk factors for polyneuropathy include degree of hyperglycemia, duration of diabetes, age, hypertension, hypertriglyceridemia, and smoking. The association between prediabetes and polyneuropathy is a subject of active debate. A number of investigators have found an increased prevalence of impaired glucose tolerance in patients with idiopathic neuropathy. However, a careful controlled case-control study of patients with idiopathic neuropathy did not show a significant association between prediabetes and neuropathy.

Early symptoms include distal numbness, burning dysesthesias, and allodynia in the feet or toes. Although discomfort is present throughout the day, it often worsens at night or with rest. Cramps are common in the calves and foot muscles. Treatment consists of tight glycemic control, which helps to prevent and slow the progression of the polyneuropathy. Large-scale controlled trials of aldose reductase inhibitors and nerve growth factor in the treatment of diabetic neuropathy have yielded disappointing results. Controlled trials of intravenous and oral preparations of the antioxidant α-lipoic acid have demonstrated its benefit on neuropathy signs and pain.

Other Neuropathies

Hypothyroidism is a common cause of median neuropathy at the wrist (CTS). Myxedematous tissue beneath the flexor retinaculum is thought to cause median nerve compression. Hypothyroidism may also cause a polyneuropathy that presents with distal dysesthesias and stocking-and-glove sensory loss. Reflexes may be diminished with a delayed relaxation phase. Electrodiagnostic and pathologic studies have shown mixed axonal and demyelinating features. Considerable improvement may occur in both CTS and hypothyroid polyneuropathy following replacement therapy.

Acromegaly may cause entrapment neuropathies due to connective tissue hyperplasia and bony overgrowth. A sensorimotor polyneuropathy may also occur associated with hypertrophic, sometimes palpable, nerves.

HIV Neuropathy

As discussed in Chapter 44 , HIV infection is associated with both acute and chronic, multifocal or generalized polyneuropathies. These include mononeuritis multiplex from vasculitic neuropathy, GBS, CIDP, and distal sensory polyneuropathy. Of all these neuropathies, distal sensory polyneuropathy is by far the most common, occurring in at least 50 percent of patients with advanced HIV. In the era before combination antiretroviral therapy, reduced CD4 ⁺ lymphocyte cell counts and increased HIV viral loads increased the risk and severity of HIV polyneuropathy. Dideoxynucleoside antiretrovrials also increase the risk of neuropathy, possibly because of toxicity to mitochondria. A polyneuropathy (usually symmetric) may occur as part of the diffuse infiltrative lymphomatosis syndrome.

Patients typically present with burning dysesthesia in feet and ankles, often with prominent allodynia. On examination, small-fiber sensory modalities are affected predominantly. Weakness related to the neuropathy is uncommon, even in advanced cases. There is no specific treatment, although a number of symptomatic treatments for neuropathic pain, including gabapentin, amitriptyline, tramadol, and lamotrigine, are effective.

Other Neuropathies

HCV infection and leprosy may cause generalized and symmetric peripheral nerve involvement, as is discussed earlier in this chapter and elsewhere in this volume.

Guillain–Barré Syndrome

Once used interchangeably with the label acute inflammatory demyelinating polyneuropathy , GBS now encompasses any acute, idiopathic inflammatory polyneuropathy producing progressive muscle weakness and areflexia, regardless of whether the underlying neuropathy is demyelinating or axonal. In many cases, a respiratory or gastrointestinal illness precedes the onset of neurologic symptoms by 1 to 3 weeks. Often paresthesias in the distal limbs herald the onset of the neuropathy. Pain similar to sciatica, myalgia, or a cramp may also occur. Rapidly progressive, symmetric weakness soon follows. Typically the weakness starts in the legs, but it may begin in the arms or face. Symptoms may progress acutely over just a few days or subacutely over as long as 4 weeks. The degree of weakness at the nadir of the progressive phase is highly variable, from mild weakness to quadriplegia with respiratory failure. Maximum deficits occur within 1 month, followed by a plateau lasting for days to weeks and rarely months. Gradual improvement occurs after the plateau phase. Prognosis is good, with a 5 percent mortality rate. Permanent disabilities remain in 5 to 10 percent of patients, mild deficits in 65 to 75 percent, and no deficit in 15 percent. The annual incidence is 1 to 2 cases per 100,000 population.

The initial assessment of GBS patients should include measurements of respiratory capacity and inspiratory force. Patients with a vital capacity of less than 20 ml/kg or a maximum inspiratory pressure less than 30 cmH ₂ O are likely to require mechanical ventilation. These measurements are much more sensitive than arterial blood gas analysis for predicting incipient neuromuscular respiratory failure. Admission to the intensive care unit (ICU) is warranted for any patient with rapidly progressive disease, significant bulbar or facial weakness, or autonomic dysfunction. Motor findings typically outweigh sensory deficits. One-third of patients may develop facial diplegia. Stretch reflexes are hypoactive or absent.

Blood tests and a lumbar puncture should be undertaken to evaluate for other causes of acute polyneuropathy or polyradiculopathy. In 50 percent of patients, an initial CSF sample will reveal an elevated protein concentration; with subsequent analysis, 90 percent of samples show increased protein, with values ranging from 55 to 250 mg/dl. The CSF is usually acellular with normal pressure. If more than 10 white cells/mm ³ are present, alternative diagnoses should be considered. Nerve conduction studies commonly show evidence of a polyneuropathy, usually demyelinating, but are sometimes normal when the patient first presents.

In Western societies, GBS is usually a demyelinating polyradiculoneuropathy. A number of infections may trigger GBS, including CMV, Epstein–Barr virus, herpesvirus, Campylobacter jejuni , Mycoplasma pneumoniae , and HIV. Rabies and swine flu vaccinations, recent surgery, and pregnancy have also been implicated as triggers for GBS. Both humoral immune responses and T-cell activation are thought to play roles in the pathogenesis. Pathologically, there is the early appearance of lymphocytes surrounding nerve vessels. This is followed by demyelination. Secondary “bystander” axonal degeneration may also occur.

In northern China, the most common GBS subtype is an acute motor axonal neuropathy (AMAN) associated with C. jejuni infection. These patients often have antibodies to gangliosides, including GM1, GD1a, and GD1b. The strains of C. jejuni associated with AMAN have GM1-like epitopes in their lipopolysaccharide membranes that contain a Gal(b1–3)GalNac moiety. Terminal motor axon branches and the internode axonolemma also contain a high concentration of this moiety. Because of molecular mimicry between these bacterial and axon antigens, those portions of the motor axons appear to be the initial targets in the autoimmune attack.

There are several other variants of GBS. The most common, the Miller Fisher syndrome , accounts for about 5 percent of all cases of GBS. Patients develop the triad of ophthalmoplegia, ataxia, and areflexia, with varying degrees of limb weakness. Almost all cases of Miller Fisher syndrome are associated with IgG antibodies to GQ1b. Other variants include weakness without paresthesias or sensory loss, pharyngeal-cervical-brachial weakness, paraparesis, facial paresis with distal paresthesias, pure ataxia, acute pandysautonomia, and acute motor-sensory axonal neuropathy (AMSAN). All variants have in common absent or diminished stretch reflexes, elevated CSF protein concentrations, and electrodiagnostic abnormalities.

For severe cases, treatment includes support in the ICU and immune-modulatory therapy. Plasmapheresis or IVIg is effective in improving short- and long-term neurologic function. The costs of plasmapheresis and IVIg are similar, and the relapse rate for IVIg is no different from that for plasmapheresis. Compared with plasmapheresis, IVIg is associated with fewer complications (e.g., hemodynamic fluctuations), is easier to administer, and is usually available in community hospitals where plasmapheresis may not be accessible. A combination of plasmapheresis followed immediately by IVIg does not lead to significantly better outcomes.

Corticosteroids are not beneficial.

Chronic Inflammatory Demyelinating Polyradiculoneuropathy

CIDP is a chronic neuropathy characterized by symmetric weakness, sensory loss, and depressed stretch reflexes. Weakness usually affects both proximal and distal muscle groups. The cranial nerves are rarely involved, but cranial neuropathies may be a presenting feature. A small percentage of patients have papilledema. The weakness must progresses beyond 2 months in order to meet an arbitrary criterion for the diagnosis of CIDP. The clinical course may be relapsing, progressive, or stepwise. There are a number of clinical variants of CIDP manifesting with either pure motor or sensory involvement or with evidence of only distal demyelination. CIDP may occur with certain medical disorders, including monoclonal gammopathies, inflammatory bowel disease, thyroid disease, HIV infection, diabetes mellitus, Charcot–Marie–Tooth neuropathies, and CNS demyelination.

The electrodiagnostic and pathologic features are similar to those of GBS. Lumbar puncture typically reveals an acellular CSF with an elevated protein level, but other laboratory tests are unremarkable. Nerve conduction studies confirm impaired nerve conduction velocities or the presence of conduction block caused by demyelination. Nerve biopsy is occasionally performed, and the findings include endoneurial perivascular inflammation with demyelination, remyelination (onion bulb formations), and secondary axonal degeneration.

Randomized, controlled trials have demonstrated the benefit of corticosteroids, plasmapheresis, and IVIg. A crossover study demonstrated that plasmapheresis and IVIg are about equally effective. The efficacy of IVIg for CIDP has also been confirmed. Azathioprine, cyclosporine, mycophenolate, and cyclophosphamide are sometimes reported to be beneficial but have not been tested in controlled clinical trials. Overall, most patients respond to treatment, but relapses are common. Only a minority of patients achieve a complete remission. Aggressive and early treatment is warranted because unchecked disease may eventually lead to axon loss and muscle atrophy for which there is no specific treatment.

Polyneuropathy Associated with Monoclonal Gammopathy of Undetermined Significance

A monoclonal gammopathy of undetermined significance (MGUS) may present as a symmetric sensorimotor polyneuropathy with variable proportions of axonal or myelin injury. The prevalence of MGUS is 1 to 3 percent in people older than 50 years. Only a minority of those with MGUS ever develop a clinically significant neuropathy, the precise number varying in different series and depending on which heavy chain is involved. Compared with neuropathy patients having IgA and IgG MGUS, patients with IgM MGUS have more sensory ataxia and more evidence of demyelination on electrodiagnostic studies. Specific antibodies can sometimes be found to myelin-specific proteins. The CSF is acellular but the protein concentration is often elevated.

Generally, neuropathies associated with MGUS respond less well to immunosuppressive or immunomodulatory therapy than idiopathic CIDP. IgG and IgA MGUS neuropathies respond better than IgM MGUS neuropathies to plasmapheresis. Improvement has also been documented with rituximab, fludarabine, and alkylating agents. Some patients have responded to IFN-α and IVIg. Long-term studies to determine the relationship between between specific immunologic markers and disease recurrence will help to develop targeted therapies.

Monoclonal Gammopathy

Multiple myeloma, Waldenström macroglobulinemia, osteosclerotic myeloma (POEMS syndrome of polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes), lymphoma, and leukemia are associated with a monoclonal gammopathy. Generally, symptoms and signs are similar to those of polyneuropathy related to an MGUS. Frequently, these neuropathies are associated with significant distal weakness and some demyelinating features on nerve conduction studies.

Amyloidosis

Amyloidosis causes a slowly progressive distal sensorimotor polyneuropathy. Distal lower-extremity pain and paresthesias are common presenting symptoms. On examination, there is usually greater impairment of small- than large-fiber sensory function. Autonomic neuropathy frequently occurs, leading to orthostatic lightheadedness, diarrhea, bladder dysfunction, and impotence. CTS is also common.

In primary amyloidosis, the amyloid fibrils consist of portions of monoclonal immunoglobulin light chains (Bence Jones protein). In almost all these patients, a monoclonal protein may be detected in either the serum or urine. Diagnosis depends on identifying amyloid deposition in tissues. An abdominal fat aspirate is probably the best initial step for establishing the diagnosis; the diagnostic yield is more than 70 percent. If this is negative, a rectal or nerve biopsy may be considered. By suppressing monoclonal light-chain production, alkylating agents extend survival in patients with primary amyloidosis. Autologous peripheral blood stem-cell transplantation is also available, but has a high morbidity and mortality. In familial amyloidosis, the fibrils are usually composed of mutant transthyretin. Molecular genetic testing for transthyretin mutations is a sensitive diagnostic test. Orthotopic liver transplantation is an effective treatment.

Paraneoplastic Neuropathy

Patients with anti-Hu (ANNA-1) antibodies usually present with a sensory neuropathy, but about 25 percent of patients present with a subacute sensorimotor polyneuropathy. Rarely, the associated neuropathy is acute, thereby mimicking GBS. Most of these patients have small-cell lung carcinoma.

Peripheral neuropathy occurs as a feature of paraneoplastic syndromes associated with anti-CV2 antibody in about 50 percent of cases. Usually it is a mixed axonal and demyelinating sensorimotor polyneuropathy, but a pure sensory neuropathy may also occur. Rarely, sensorimotor neuropathies have been described with anti-Ri (ANNA-2) and anti-Yo (PCA-1) antibodies.

Vitamin B ₁ (Thiamine) Deficiency

Thiamine deficiency is uncommon in industrialized countries. Inadequate consumption may occur in the context of chronic alcohol abuse, total parenteral nutrition, prolonged vomiting, and bariatric surgery. Initial neuropathic symptoms (dry beriberi) include burning dysesthesias in the feet with mild sensory loss. Fatigue, muscle aches, and cramps in the lower extremities are common. Although progression is usually subacute to chronic, the neuropathy sometimes develops over a few days. In severe cases, there may be significant weakness of ankle dorsiflexion and finger and wrist extension in addition to stocking-glove sensory deficits. The recurrent laryngeal nerve may become involved, causing hoarseness. With thiamine supplementation, the neuropathy typically improves, albeit modestly. Further details are provided in Chapter 15 .

Vitamin B ₆ (Pyridoxine) Deficiency

Deficiency of vitamin B ₆ (pyridoxine) causes a distal axonal sensorimotor polyneuropathy. It is a known complication of taking the prescription medications isoniazid and hydralazine. If these medications are prescribed, oral supplementation of vitamin B ₆ at daily doses of 50 to 100 mg is advised. Vitamin B ₆ deficiency may also occur with chronic peritoneal dialysis or alcoholism.

Overdosing with vitamin B ₆ may cause an ataxic sensory neuronopathy associated with degeneration of posterior root ganglia neurons. Stretch reflexes are hypoactive or globally absent. Most patients have numbness, paresthesia, and gait ataxia. Daily ingestion of as little as 200 mg per day has been associated with the development of a peripheral neuropathy in some instances.

Vitamin B ₁₂ (Cobalamin) Deficiency

The classic neurologic presentation of vitamin B ₁₂ deficiency is combined degeneration of the dorsal and lateral columns of the spinal cord. Patients present with distal numbness, paresthesias, and, occasionally, dysesthesias. Compared with patients with idiopathic distal polyneuropathy, patients with vitamin B ₁₂ deficiency are more likely to have concomitant involvement of the upper and lower extremities, initial symptom onset in the hands, and a sudden onset of symptoms. In more advanced cases, paraparesis occurs with extensor plantar responses. Malabsorption is the cause of most cases; it may be due to pernicious anemia, gastric or bowel surgery, or inflammatory bowel disease. Neurologic manifestations of vitamin B ₁₂ deficiency may occur without anemia or elevated mean corpuscular volume. Testing for elevations of serum homocysteine and methylmalonic acid is helpful when the vitamin B ₁₂ level is borderline low. With early treatment, the paresthesias may improve, but loss of large-fiber sensory axons is often permanent. Traditionally, vitamin B ₁₂ is supplemented with weekly to monthly intramuscular injections. Because individuals with pernicious anemia still absorb small amounts of vitamin B ₁₂ , oral supplementation at a dose of 1,000 to 2,000 μg daily may be equally effective.

Vitamin E Deficiency

Vitamin E deficiency presents as a spinocerebellar ataxia with polyneuropathy. It usually results from lipid malabsorption; errors of vitamin E absorption or transport are less common causes. Pathologically, there is degeneration of sensory axons, posterior root ganglia, posterior columns, and spinocerebellar tracts. The diagnosis is made by measuring serum α-tocopherol levels. Proper supplementation depends on the underlying cause of the deficiency.

Copper Deficiency

Copper deficiency has been associated with a myeloneuropathy characterized clinically by limb paresthesia and spastic paraparesis. Patients have deficits of large-fiber sensation, and many have extensor plantar responses. Often patients have microcytic anemia and neutropenia. Many patients have had prior gastric surgery. Some cases have been linked to excessive zinc levels, which are known to cause copper deficiency. Following copper supplementation, some patients show neurologic improvement.

Alcoholic Neuropathy

A distal axonal polyneuropathy is a common complication of chronic alcoholism, occurring in approximately 10 to 50 percent of patients, depending on the study and diagnostic criteria. Superficial sensation is principally impaired and dysesthesias are common. Pathologically, there is loss of sensory and motor axons. The pathophysiology is not fully understood but may involve direct toxicity of alcohol on peripheral nerves; vitamin deficiencies, including thiamine deficiency, are probable contributing factors. Treatment involves abstinence and vitamin supplementation. Prognosis is good for mild to moderate neuropathy after 3 to 5 years of abstinence. Further details are provided in Chapter 33 .

Neuropathies Associated with Heavy Metal Exposure

Severe lead poisoning produces a subacute, asymmetric, predominantly motor neuropathy that preferentially affects the wrist and finger extensors. Footdrop is another common manifestation. Prognosis for recovery is good if the lead exposure is eliminated. Abdominal pain, anemia, encephalopathy, and mild sensory deficits may also occur.

Arsenic ingestion typically causes acute abdominal pain followed in 5 to 10 days by dysesthesias in the hands and feet. This is followed by an axonal polyneuropathy presenting as symmetric ascending weakness. The weakness may progress over several weeks. Recovery depends on the degree of axonal loss.

Additional details about the neurologic complications of heavy metal exposure are given in Chapter 35 .

Medications and other Chemicals

Medications and chemicals generally cause a subacutely progressive symmetric, distal, and length-dependent neuropathy, with sensory and motor axonal degeneration. A careful review of occupational exposures to toxins as well as exposures related to hobbies usually leads to candidate toxins. If the exposure is terminated, the neuropathy may continue to worsen for days to weeks (“coasting”) before its course is arrested. A number of toxins have been incriminated ( Table 59-6 and Chapter 35 ).

Adrenomyeloneuropathy

Adrenomyeloneuropathy is a milder phenotype of adrenoleukodystrophy, the X-linked disease associated with degeneration of white matter and the adrenal cortex caused by mutations of the ABCD1 gene. Adrenomyeloneuropathy may present from childhood to middle age, usually in men, but occasionally in women. Patients present with a spastic paraparesis, sphincter abnormalities, and sexual dysfunction with or without symptomatic adrenal insufficiency or cognitive problems. The neuropathy is responsible for weakness and depressed ankle reflexes. Nerve conduction studies typically have shown a mixed axonal and demyelinating polyneuropathy. Testing for very-long-chain fatty acids is the initial diagnostic test for both males and females. Bone marrow transplantation is an effective treatment for those with MRI evidence of brain involvement and minimal neuropsychologic findings. Reduction of hexacosanoic acid by Lorenzo’s oil remains an investigational therapeutic approach for adrenoleukodystrophy.

Fabry Disease

Fabry disease is an X-linked recessive disorder of the gene encoding α-galactosidase A. Deficiency of this lysosomal enzyme causes widespread accumulation of globotriaosylceramide (GL-3) in cells throughout the body. Males present in adolescence with crises of severe pain in the extremities, vascular cutaneous lesions (angiokeratomas), hypohidrosis, corneal and lenticular opacities, and proteinuria. Renal function gradually deteriorates over time, leading to end-stage renal disease. In middle age, cardiovascular and cerebrovascular disease is another cause of significant morbidity and mortality. Patients have a distal small-fiber polyneuropathy with normal nerve conduction velocities. Pain may respond to phenytoin, carbamazepine, or gabapentin. The diagnosis is usually made by demonstration of deficient α-galactosidase A activity in plasma, leukocytes, or cultured cells. Hemodialysis or renal transplantation is often necessary. An expert panel has recommended that enzyme replacement therapy be initiated as early as possible for all males and for females with significant disease.

Porphyria

Inherited defects in the hepatic enzymes responsible for heme synthesis—the hepatic porphyrias—may be associated with acute episodes of CNS and peripheral nervous system dysfunction. These disorders include acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria. The erythropoietic porphyrias are associated with photosensitivity but not neurologic disease. Between attacks, patients with hepatic porphyrias are normal. An attack is typically triggered by a drug that activates the hepatic cytochrome P-450 system, although hypoglycemia and hormonal factors may also contribute.

Clinically, patients present with acute, severe colicky abdominal pain accompanied by psychiatric disturbances. Often, medications used to treat pain and anxiety only exacerbate the attack by inducing certain hepatic enzymes. A painful, often asymmetric axonal neuropathy typically appears 2 to 3 days after the onset of abdominal pain. The weakness frequently begins in the upper extremities. Proximal or distal muscle groups may be involved. Reflexes are usually lost in proportion to weakness, unlike the early areflexia typically seen in GBS. Despite the pain, sensory deficits are usually mild and patchy. The combination of abdominal pain and neuropathy makes the clinical presentation similar to heavy metal intoxication.

Screening for the hepatic porphyrias involves an analysis of the heme precursors in urine. The results of the urinalysis may be normal in asymptomatic carriers. Treatment includes stopping all medications that could potentially exacerbate the attack and infusing heme. Although recovery from the psychiatric disturbances is typically rapid, recovery of the peripheral nerves depends on the severity and extent of the axon loss; ultimate recovery of the peripheral nervous system is generally good.

Refsum Disease

Refsum disease is an autosomal-recessive disorder characterized by anosmia, retinitis pigmentosa, deafness, ataxia, ichthyosis and neuropathy. Symptoms may begin at any age. Over 90 percent of cases are associated with mutations of the phytanoyl-CoA hydroxylase gene ; less than 10 percent are associated with mutations of the PEX7 gene. The consequence of these mutations is a build-up of phytanic acid in various tissues. The presence of high levels of serum phytanic acid (>200 μmol/L) establishes the diagnosis. Phytanic acid deposition in Schwann cells and the endoneurial space leads to a distal, symmetric sensorimotor neuropathy. Reduction of phytanic acid concentrations by dietary restriction, plasmapheresis, or lipid apheresis improves ichthyosis, sensory neuropathy, and ataxia but may not benefit the retinitis pigmentosa, anosmia, and deafness.

Tangier Disease

Tangier disease is a rare autosomal-recessive disorder caused by mutations in both alleles of the adenosine triphosphate–binding cassette A1 gene ( ABCA1 ). The protein deficiency causes decreased lipid removal from cells, widespread tissue accumulation of cholesteryl esters, and the absence of plasma high-density lipoproteins (HDLs). Absent high-density lipoproteins with normal triglyceride level and the presence of enlarged orange tonsils differentiates Tangier disease from other lipoprotein disorders. Patients may develop corneal opacities or hypersplenism. Despite the high-density lipoprotein deficiency, atherosclerosis does not develop earlier than normal. Polyneuropathy may take one of three forms: asymmetric, relapsing-remitting sensorimotor mononeuropathies, usually associated with normal conduction velocities; symmetric, slowly progressive distal polyneuropathy; and a slowly progressive neuropathy affecting the face and upper limbs with distal hand weakness and facial diplegia and accompanied by dissociative sensory loss that may mimic the presentation of a syrinx. There is currently no specific treatment for Tangier disease.