Dominant psychiatric manifestations in Wilson's disease: a diagnostic and therapeutic challenge!

INTRODUCTION: Recognition of psychiatric manifestations of Wilson's disease (WD) has diagnostic and therapeutic implications. OBJECTIVE: To describe the clinical features and psychopathology of patients with WD who had initial or predominant psychiatric manifestations. PATIENT AND METHODS: Records of 15 patients with WD (M:F: 11:4), from a large cohort of 350 patients, with predominant psychiatric manifestations at onset were reviewed. Their initial diagnosis, demographic profile, family history, pre-morbid personality, clinical manifestations, treatment and outcome were recorded. RESULTS: Their mean age at diagnosis was 19.8+/-5.8 years. Six patients were born to consanguineous parentage and two patients each had family history of WD and past history of psychiatric illness. Diagnosis of WD was suspected by detection of KF rings (all), observing sensitivity to neuroleptics (n=2), history of jaundice (n=2) and family history suggestive of WD (n=9). Psychiatric manifestations could be classified as affective disorder spectrum (n=11) and schizophreniform-illness (n=3). While the psychiatric symptoms improved in five patients with de-coppering therapy, seven patients needed symptomatic treatment as well. Three of the four patients who responded to de-coppering therapy were sensitive to neuroleptics. Long-term follow up of 10 patients revealed variable recovery. CONCLUSIONS: Young patient with psychiatric manifestations with clues like history of jaundice, family history of neuropsychiatric manifestations and sensitivity to neuroleptics should be evaluated for WD to avoid delay in diagnosis and associated morbidity. SIGNIFICANT OUTCOMES: The study reemphasizes the importance of behavioral manifestations in Wilson disease in terms of diagnosis and management difficulties. LIMITATIONS: Retrospective nature of the study.

Wilson's disease: a clinico-neuropathological autopsy study.

Wilson's disease (WD), a familial neurological disorder involving the brain and liver secondary to altered copper metabolism, is common in South India. In view of the paucity of studies on this condition, the pathomorphological features of eight cases of WD were studied in detail at autopsy (brain alone, 1; brain and liver biopsy, 1; brain and visceral organs, 6), and are described with a discussion of the differential features of the neurological and hepatic forms. Of the six patients presenting with neurological manifestations, five had central pontine myelinolysis, five had subcortical white matter cavitations, four had putaminal softening, and six had variable ventricular dilatation, unlike the hepatic form. The presence of Opalski cells and pontine myelinolysis appear to be specific to the neurological form of WD. Liver abnormalities were observed in all cases (cirrhosis, 6; steatosis, 4; chronic active hepatitis, 2). Contrary to the rubric 'hepatolenticular degeneration', involvement of the lenticular nucleus was not universal, and nor was the pathology restricted to these anatomical areas.

Hypertrophic cranial pachymeningitis in countries endemic for tuberculosis: diagnostic and therapeutic dilemmas.

Hypertrophic cranial pachymeningitis (HCP) is an uncommon disorder with few studies correlating clinical, imaging and histopathological features. The aim of this study was to describe clinical and laboratory observations and therapeutic options of patients with HCP. Eleven patients with HCP (M:F 6:5; age range, 23-52 years) were evaluated over 10 years. Etiology was ascertained by MRI and laboratory tests and confirmed by biopsy of meninges and/or brain (7), nasal mucosa (1), mediastinal lymph node (1), muscle (2) or conjunctiva (2). Salient clinical features were headache (7), multiple cranial neuropathies (8), visual disturbances (6), seizures (2) and hemiparesis (2). Abnormal tests included: rapid erythrocyte sedimentation rate (3), positive serum venereal disease testing (1), chest CT abnormalities (4/6) and positive Mantoux test (2/5). Cerebrospinal fluid changes (10/11) revealed the following: cell count 0-47/mm(3); protein 14-95 mg/mL; and glucose of 44-79 mg/mL. Contrast MRI revealed a variable extent of thickened dura mater in all patients. Histopathology (n=11) confirmed chronic inflammation (100%) and provided specific etiology in six (vasculitis [2], sarcoidosis [2], tuberculosis [1], Wegener's granulomatosis [1]). Treatment included steroids only (4), anti-tubercular therapy with steroids (5), penicillin (1) and cyclophosphamide and plasmapheresis (1). During follow-up (27.0+/-26.3 months) there was significant recovery (9/9). On serial imaging (4), the lesion remained the same in three and resolved partially in one patient. HCP, despite frequently posing diagnostic and therapeutic challenges, has favorable outcome when treated appropriately.

Wilson disease: description of 282 patients evaluated over 3 decades.

The clinical manifestations of Wilson disease (WD) are varied and challenging. We conducted the current study to present the phenotypic characteristics and follow-up for a large cohort of patients with WD. We reviewed the medical records of 282 cases of WD (male:female ratio, 196:86) for clinical features, investigations, treatment, and outcome data. The clinical presentations were as follows: hepatic, 42 (14.9%); hepato-neurologic, 10 (3.5%); neurologic, 195 (69.1%); pure psychiatric, 7 (2.4%); osseomuscular, 6 (2.1%); and "presymptomatic," 15 (5.3%). Mean age was 15.9 years. Presymptomatic patients and those with the hepatic form of WD were younger and patients with osseomuscular and psychiatric forms were older than neurologic patients. The mean duration of illness at the time of diagnosis was 28 months. Predominant neurologic features were as follows: parkinsonism, 62.3%; dystonia, 35.4%; cerebellar, 28%; pyramidal signs, 16%; chorea, 9%; athetosis, 2.2%; myoclonus, 3.4%; and behavioral abnormalities, 16%. Kayser-Fleischer (KF) rings were seen as follows: neurologic patients, 100%; hepatic patients, 86%; and presymptomatic patients, 59%. Positive family history was noted in 47% and consanguinity in 54%. Patients born of consanguineous parents had an earlier age of onset and shorter duration of illness before presentation. Serum ceruloplasmin was decreased in 93% and 24-hour urinary copper excretion was increased in 70% of patients. Neuroimaging (computed tomography/magnetic resonance imaging) and electrophysiologic abnormalities were seen in many patients. Overall, 195 patients were on D-penicillamine therapy and 182 on zinc sulphate. Follow-up data, available for 225 patients, for a mean duration of 46 months, revealed improvement in 176, no change in 20, and deterioration in 6. Twenty-three patients died. To conclude, despite increased awareness and recognition and significant inroads into therapeutic frontiers, follow-up remains poor in developing countries and a return to previous level of functioning is not universal.

Extensive cortical magnetic resonance signal change in proximal urea cycle disorder.

The authors report a 3-year 8-month-old girl presenting with episodic hyperammonemic encephalopathy probably due to a proximal urea cycle disorder. The magnetic resonance imaging (MRI) of the brain performed during the third episode revealed extensive and diffuse cerebral cortical signal changes with sparing of occipital cortex. It is believed that intracerebral accumulation of glutamine mainly in astrocytes is the major cause of the encephalopathy. This results in astrocyte swelling, brain edema, intracranial hypertension, and cerebral hypoperfusion.

Menkes syndrome presenting as myoclonic seizures: neuroimaging and EEG observations.

The authors report an 11-month-old boy with Menkes kinky hair disease who presented with global delay in acquiring milestones and repeated myoclonic jerks. He had scanty, hypopigmented scalp hairs with steely wool-like texture and intervening zones of alopecia. There was low serum ceruloplasmin (5 mg/dL) and copper (24.2 microg/dL). Neuroimaging of the brain revealed marked cerebral atrophy and significant delayed myelination. Magnetic resonance angiography showed tortuous cerebral and neck blood vessels. There was poor therapeutic response to symptomatic treatment.

Dysmyelinating neuropathy in benign form of megalencephalic leukoencephalopathy with subcortical cysts: a novel observation from south India.

A 37-year-old gentleman presented with macrocephaly since early childhood and progressive impairment of motor and cognitive functions. Magnetic resonance imaging revealed extensive white matter involvement and frontotemporal subcortical cysts. Absent ankle jerk and abnormal nerve conduction study raised a possibility of associated peripheral neuropathy. Sural nerve biopsy was suggestive of dysmyelinating neuropathy. This report serves to expand the clinical spectrum of this rare leukodystrophy.

Hepatic myelopathy: a rare complication following extrahepatic portal vein occlusion and lienorenal shunt.

A 19-year-old gentleman presented with slowly progressive spastic paraparesis, 2 years after the therapeutic lienorenal shunt for portal hypertension secondary to cirrhosis and portal vein occlusion. After 2 years of initial evaluation, the motor functions had not worsened further. He did not have any obvious clinical or EEG features of hepatic encephalopathy. Other causes for myelopathy were ruled out. Contribution of portal vein occlusion to portosystemic shunting has not been reported previously in patients with 'hepatic myelopathy.' This uncommon complication needs to be considered in patients with shunt surgery for relieving portal hypertension.

Prognostic factors in patients presenting with severe neurological forms of Wilson's disease.

BACKGROUND: Wilson's disease (WD), a metabolic disorder, is believed to be potentially reversible, even in its severe form. However, some patients do not respond to treatment. AIM: To analyse prognostic factors in severe WD. DESIGN: Retrospective audit. METHODS: A total of 140 patients were regularly followed from February 2002 to May 2004. Twenty-nine (18 males, 11 females) had severe disease, as defined by Modified Schwab and England Activities of Daily Living score (MSEADL) of < or=50% or Chu stage of 3. We analysed their clinical, laboratory and MRI features with respect to prognosis. RESULTS: For the severe form, mean age at symptom onset was 11.5 +/- 6.4 years, and at diagnosis, 13.3 +/- 7.0 years. Mean Neurological Symptom Score (NSS), Chu stage, and MSEADL were 26.5 +/- 8.2, 2.7 +/- 0.5 and 24.8 +/- 17.4, respectively. Twenty-one patients underwent MRI; 14 had repeat MRI. Following treatment, 14 (group A) had progressive worsening, including death in two, while 15 (group B) had sustained clinical improvement. Baseline demographic, clinical and laboratory features and MRI scores did not significantly differ between the two groups. However, diffuse white-matter abnormalities were more extensive in group A. Full-dose initial penicillamine therapy could have contributed to worsening in four patients. Drug compliance was poor in both groups but resumption of treatment did not benefit patients in group A. Serial MRI showed regression of lesions only among patients with clinical improvement. DISCUSSION: Severe WD remains a therapeutic challenge, with early diagnosis and treatment are essential. Specific MRI observations, a 'start low-go slow' regimen for penicillamine, and compliance may have prognostic significance. In absence of clinical predictors, genetic attributes need to be explored.

Is low serum tocopherol in Wilson's disease a significant symptom?

BACKGROUND: Free radical mediated injury is increasingly recognized in many metabolic diseases including Wilson's disease (WD). Use of antioxidants as an adjunctive therapy in WD may have therapeutic significance. AIM: The aim of the study was to correlate serum levels of tocopherols with serum copper and ceruloplasmin and clinical status of these patients. METHODS: Serum levels of tocopherol of were measured spectrophotometrically using the Emmerie-Engel reaction in 34 patients from a large cohort of WD being followed up at a tertiary care center. RESULTS: Majority of patients were male (M/F=23:11). The mean serum copper was 43.6+/-26.2 microg/dl (range=10-121 microg/dl) and serum ceruloplasmin was 5.6+/-5.5 mg/dl (range=0-30 mg/dl). The mean serum tocopherol level was 0.68+/-0.18 mg/dl (range=0.23-1.14 mg/dl) and compared to the control (1.07+/-0.17 mg/dl), nearly 59% of patients had decreased levels (p<0.001). No significant correlation was noted between low serum tocopherol levels and serum copper levels, Mini Mental Status Examination (MMSE) scores and CHU staging. However, serum tocopherol levels were lower in patients with relatively short duration of treatment (7.8 years vs. 12.4 years). CONCLUSION: Decreased levels of serum tocopherol were detected in 59% of patients compared to controls. However, low tocopherol levels did not correlate with clinical status or biochemical parameters of WD, except for relatively shorter duration of treatment. Further studies, especially in newly diagnosed patients, need to be done to validate the role of low tocopherol levels in Wilson's disease.

Neurological manifestations of Ehlers-Danlos Syndrome.

Ehlers-Danlos Syndrome (EDS) is more identified for its cutaneous features but its neurological manifestations have not received the focused attention. Four patients of Ehlers-Danlos Syndrome (EDS) with neurological manifestations were evaluated for phenotypic data. These four men were from three families and two had consanguineous parentage. The mean age at onset and presentation of neurological symptoms were 10.5 years and 19 years respectively. Patient 1 presented with bilateral optic atrophy, sensorineural deafness, cerebellar ataxia and neuropathy. Patient 2 had marfanoid habitus, chorea and cerebellar ataxia. Patient 3 had action and percussion myotonia, wasting and weakness of sternocleidomastoid and distal limb muscles. Patient 4 had action myotonia, mirror movements of both hands and neuropathy. MRI of brain showed right parietal polymicrogyria. Neuroaxis involvement at multiple levels in EDS may have prognostic significance.

Fibromuscular dysplasia with dissection of basilar artery presenting as "locked-in-syndrome".

We report on a young man with fibromuscular dysplasia involving the basilar artery detected at autopsy. He presented with sudden onset of stroke, and the lesion was complicated by thrombosis and dissection of the vessel wall. The organizing thrombotic lesion of the basilar artery was responsible for the ventral pontine infarct that resulted in "locked-in syndrome."

Sympathetic skin response: a decade later.

Sympathetic skin response (SSR) is a simple, reproducible test of function of a polysynaptic reflex having diverse afferents, a common efferent pathway through the spinal cord, pre and post-ganglionic sympathetic fibers and with sweat glands as effectors. The reflex is co-ordinated in the posterior hypothalamus or upper brainstem reticular formation. It has been used in a variety of disorders of peripheral and central nervous system. Methodology, possible anatomic substrates, changes in SSR in various diseases and their correlation with clinical features of dysautonomia, bed side tests for dysautonomia and other electrophysiological parameters are critically evaluated. Almost a decade after the start of its widespread clinical utilization, several aspects of SSR remain inconclusive. A consensus as to what change in SSR to consider abnormal is yet to be reached. Though its ease of application supersedes a variety of other autonomic function tests, relying only on SSR changes for prognostication or therapeutic decisions appears impracticable. A battery of tests is thus a necessity.

Sympathetic skin response in acute sensory ataxic neuropathy.

Sympathetic skin response (SSR) is a recently described objective method of studying sudomotor sympathetic nerve function and has been studied in a variety of peripheral neuropathies. We report SSR changes in nine patients with acute sensory ataxic neuropathy (ASAN). All had severe sensory and mild motor nerve conduction abnormalities; five had dysautonomia. SSR, elicited by electric shock and cough stimuli, was absent in three patients. Latency was normal in all when SSR was present. Two patients had SSR amplitude of 0.2 mV or less. Absence of SSR did not correlate with dysautonomia, absence of sensory nerve action potential or motor nerve conduction abnormalities. Follow up SSR studies revealed return of absent SSR in one patient over a period of 3 months, despite persistence of ataxia. To our knowledge, this is the first report of SSR changes in ASAN.

Successful pregnancies and abortions in symptomatic and asymptomatic Wilson's disease.

BACKGROUND: There are only a few reports regarding the fertility and outcome of pregnancy in Wilson's disease (WD) and none from India. The authors in this study discuss various aspects of fertility in 16 women with WD. METHODS: Retrospective analysis of data from a large cohort of WD, being followed at a tertiary care center. RESULTS: Sixteen patients had conceived on 59 occasions with 30 successful pregnancies, 24 spontaneous abortions, 2 medical terminations of pregnancy and 3 still births. Diagnosis of WD was established after conception in 10 presymptomatic patients while six patients were already on treatment. Among these 16 patients, 9 had history of spontaneous abortions and 12 had successful pregnancies. None of the clinical features of WD changed during pregnancy, with or without treatment. All the 30 babies were full-term and delivered healthy. CONCLUSION: Recurrent abortions are common especially in women with untreated Wilson's disease. However, successful pregnancies and uneventful full-term delivery may occur in mothers of WD on treatment and in undiagnosed, undetected presymptomatic patients. Pregnancy does not seem to have adverse effect on the clinical course of Wilson's disease. Teratogenecity was not seen in the present series with low-dose penicillamine and zinc sulphate.

HIV-1 clade-C-associated "ALS"-like disorder: first report from India.

A patient of ALS-like disorder in an HIV-1 clade-C-infected heterosexual male is being reported. A 37-year-old gentleman presented with subacute, progressive asymmetrical onset of weakness and wasting of upper limbs associated with brisk muscle stretch reflexes and without any sensory or sphincter involvement. While nerve conduction tests were normal, the EMG of proximal and distal limb muscles on both sides revealed evidence of denervation and reinnervation. Routine blood and urine tests and investigations for underlying causes of motor neuron disease were noncontributory. He was HIV-1, subtype clade C seropositive. A diagnosis of HIV-related anterior horn cell disease was considered and zidovudine, lamivudine and nevirapine were started. After 1 month, there was a subjective improvement of 10% and objective improvement in strength of muscles of proximal upper limb on both sides by one grade power on MRC scale. Reports of amyotrophic lateral sclerosis (ALS)-like illness in HIV are sparse. The reversibility of "ALS"-like features in this subgroup of patients might offer an insight into the pathogenesis of amyotrophic lateral sclerosis. This is a first report of ALS-like illness caused by subtype C of HIV-1 strain.

Electromyography in near-total laryngectomy.

OBJECTIVE: To investigate the dynamics of speech shunt muscle in patients with Pearson near-total laryngectomy by needle electromyography and correlation of ability to activate shunt muscle with speech production. DESIGN AND SETTINGS: Prospective study of patients with near-total laryngectomy at 2 hospital-based academic tertiary care centers. PARTICIPANTS AND INTERVENTION: Fourteen patients with near-total laryngectomy were subjected to percutaneous needle electromyographic study of the shunt muscle. MAIN OUTCOME MEASURES: Speech ability, electromyographic evidence of viable muscle in shunt wall, and ability to activate shunt muscle were recorded. RESULTS: Twelve of 14 patients had good speech; 11 had evidence of viable shunt muscle; and 9 were able to activate muscle by phonation, swallowing, or deep breathing, indicating preserved innervation. Six of the 12 patients with speech ability and 1 of the 2 patients without speech ability were able to recruit motor units during attempted phonation. CONCLUSIONS: Electromyography demonstrated viable muscle with retained innervation in 64% of the patients with near-total laryngectomy, proving its "dynamic" nature. However, the usefulness of shunt muscle activation in speech and prevention of aspiration needs further confirmation.

Peripheral neuropathy in subacute sclerosing panencephalitis--immunohistochemical and ultrastructural evidence.

A patient with SSPE who had prominent diffuse white matter hypodensities on CT scan indicating central white matter demyelination and nerve conduction abnormalities suggestive of peripheral neuropathy is reported. Diagnosis was established by demonstration of elevated CSF measles antibody titers and presence of virus antigen and nucleocapsid in peripheral nerve. To our knowledge, this is the first report of demonstration of measles virus nucleocapsides and antigen in the peripheral nerve in SSPE.

Co-occurrence of Wilson's disease and glioblastoma multiforme--is it a chance association?

We report a patient with glioblastoma multiforme who was subsequently diagnosed to have Wilson's disease. Immunohistochemical studies of the tumor revealed high (> 60%) labeling index for p53 and Rb retinoblastoma protein. Whether this association is like the co-occurrence of retinoblastoma and Wilson's disease due to possible somatic mutation in chromosome 13 needs to be explored.

Infections in neurology and neurosurgery intensive care units.

Nosocomial infections are common among hospitalized patients, more so in intensive care units (ICU). They contribute significantly to morbidity, mortality and cost of care. Few studies address the issue of nosocomial infections in Neurology and neurosurgery ICUs, (NNICU) and data from other ICUs probably cannot be extrapolated to acutely ill neurologic patients. While the incidence of urinary tract infections and catheter related infections may be similar to those in other ICUs, comatose patients may be at a greater risk of nosocomial pneumonia. Certain nosocomial infections are peculiar to NNICU and appear to be associated with higher mortality and morbidity. A systematic approach to evaluation of new episodes of fever, informed use of empirical antibiotics in the context of prevailing drug sensitivities and developing a hospital infection control program are methods crucial to controlling and preventing nosocomial infections. Infections in the intensive care unit (ICU) have been under intense study over the last two decades. Nosocomial infections are common and to a large extent, preventable. However, an established infection by multidrug resistant bacteria is difficult to treat and results in a high mortality, morbidity and cost of care. This article addresses nosocomial infections in the context of the Neurology and Neurosurgery ICU (NNICU).