Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.258035
Source of Support: None, Conflict of Interest: None
Shapiro syndrome is a very rare neurological disorder consisting of a triad of corpus callosum agenesis, episodes of hyperhidrosis, and hypothermia. Here we describe a patient of Shapiro syndrome who repeatedly presented with catatonia and thrombocytopenia in a span of three years. There were several diagnostic difficulties initially due to a lack of knowledge about the exsitence of Shapiro syndrome.
A 28-year male patient, educated until the eighth standard, married, autorickshaw driver, presented for the first time to the emergency medicine department of our tertiary care hospital in North India with an abrupt-onset altered sensorium in January 2013. He had irrelevant talk, poor oral intake, unresponsiveness with incontinence of urine and faeces for 2 days. There was a history of episodes of hyperhidrosis and lethargy from 2006. There was no history of substance abuse and any other relevant past, family, or medical history. He was observed to be drowsy, restless, had perseveration of speech, and was disoriented to time, place, and person. His general physical examination and systemic examination were unremarkable. In his investigations, the platelet counts were 50,000/L and total leucocyte counts were 3400/L, which were both low. The remaining investigations including the blood counts, serum electrolytes, renal function tests, and liver function tests were within the normal range. He was given intravenous (i.v.) fluids and inj. lorazepam 4 mg for restlessness. Pending cerebrospinal fluid (CSF) analysis and magnetic resonance imaging (MRI) brain reports, he was also given i.v. phenytoin, antibiotics, and antimalarials empirically for acute onset altered sensorium. He was given tab. haloperidol 0.5 mg TDS for delirium after the psychiatry consultation on the third day. His MRI brain report came on the third day and it showed an incidental finding of complete agenesis of corpus callosum with colpocephaly [Figure 1] and [Figure 2]. His CSF culture was sterile. Due to these reports, all i.v. injections were stopped. Within 6 days, his condition improved spontaneously. His platelet counts also increased to 1.4 x 105/L; the remaining of the blood counts normalized and he was discharged in 6 days. He regained his normal socio-occupational functioning. He started consulting another hospital and was given cap. venlafaxine 75 mg/day suspecting depression. Later in 2013, he was diagnosed with hypothyroidism and was prescribed tab. thyroxine 37.5 g/day. The patient again became symptomatic in October 2015 while being compliant to treatment. The illness was initially characterized by episodes of hyperhidrosis lasting for 10–15 min, occurring several times daily, with associated extreme fatigue, leading to insomnia, decreased interaction, and decreased work output. These manifestations, however, were yet again thought to be a part of depression, and venlafaxine was increased with which there was no improvement.
In January 2016, he had a poor oral intake, prolonged periods of immobility of body, and incontinence of urine and faeces. His CSF examination was acellular, sterile, and with normal levels of sugar and protein. His MRI brain was repeated and showed no additional findings. He was admitted to the psychiatry ward in February 2016 for management. On admission, the patient was observed to have mutism, negativism, psychological pillow, and stupor. His Bush–Francis catatonia rating scale (BFCRS) score was 15 at admission. Investigations revealed normal serum electrolytes, blood sugar, renal function tests, and electrocardiography (ECG). His platelet count was, however, 30,000/L, while rest of the blood counts were normal. Dengue serology, upper abdomen ultrasound, bleeding and clotting tests were done which were within normal limits. Screening was done for antibodies against human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) antigen, which was negative. His thyroid function tests were done and the reports revealed normal levels of T3, T4, thyroid stimulating hormone (TSH), and anti-thyroid peroxidase (TPO) antibodies. His electroencephalography (EEG) showed diffuse slowing. He was initially given inj. lorazepam 6 mg/day for catatonia with which he started improving. He started eating, his mobility improved, and he became communicative. Tab. thyroxine 37.5 g/day was continued. Over the next few days, it was observed that the patient had impaired recent memory and poor attention. He was also observed to have episodes of profuse sweating in the ward lasting for 10–15 min every few hours which were just recorded, but the temperature monitoring was not done in relation to the episodes of hyperhidrosis at that time. His Bush-Francis Catatonia Rating Scale (B FCRS) score decreased to 4 on the sixth day of admission, yet his mini-mental state examination (MMSE) score was 10/30. His cognitive functions were assessed using PGI battery of brain dysfunction (PGIBBD); it showed deficits in verbal retention, visual retention, recognition, and arithmetic abilities with a total dysfunction rating of 23 indicating significant cognitive deficits. No evidence of depressive cognition or psychosis could be found on serial mental status examinations. His platelet count improved slightly to 50,000/L within a week. He was suspected to have anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis due to the presence of catatonia and he was given inj. methylprednisolone 1 g i.v. for 5 days and inj. levetiracetam 3 g/day. He recovered completely and was discharged on the 17th day of admission when his MMSE score was 27/30 and the BFCRS score was 0. His repeat dysfunction rating score on PGIBBD became 8, which was below the cutoff level of 20, indicating no significant cognitive impairment. His platelet count improved spontaneously to 2 x 105/L. Later, his serum anti-NMDAR antibody report came out to be negative.
The patient had another relapse in June 2016. He developed episodes of hyperhidrosis, lethargy, and decreased appetite. He was again admitted for diagnostic evaluation in the beginning of July 2016 for a few days. He did not improve on inj. methylprednisolone this time. The patient's serum voltage gated potassium channel-complex (VGKC) antibody test was negative. His platelet count steadily started falling again from 2.16 x 105/L to 1.6 x 105/L. His history was reviewed and a literature search was done on PubMed quoting “hyperhidrosis and thrombocytopenia” where we came across the term “Shapiro syndrome.” Hence, he was readmitted to the psychiatry ward in July 2016 for assessment of hypothermia. Hypothermia is defined as a core body temperature below 35°C or 95°F. In our patient, we observed that during the episodes of hyperhidrosis, his core body temperature would fall down to 92-93 degree F. Thus, he fulfilled the triad of corpus callosum agenesis, hypothermia and hyperhydrosis confirming the diagnosis of Shapiro syndrome. In this admission he was also observed to have hypotension (BP 80/60 mmHg) which was controlled by giving i.v. fluids. He also had intermittent sinus bradycardia as recorded on electrocardiogram (ECG) which showed a heart rate of 50 beats per minute. This time he was given tab. clonidine 0.3 mg/day when his pulse rate was normal. But with this medication, he did not improve. Then he was given tab. cyproheptadine 6 mg/day with which he improved significantly. Upon discharge, he regained his normal socio-occupational functioning.
Individuals with the congenital anomaly of agenesis of corpus callosum may remain asymptomatic throughout life. Some of them may have associated ocular anomalies, or symptoms due to associated lesions in other areas of the central nervous system, or some may develop mental retardation or seizures. Shapiro syndrome has been reported to occur in about 2% of patients with corpus callosum agenesis. Approximately 50 previous cases of Shapiro syndrome have been described in literature.,,,,,,,,,,,,,,,,,,,,, A compilation of earlier case reports of Shapiro syndrome which are available in English medical literature are shown in [Table 1]. The age of presentation of Shapiro's syndrome can be highly variable, ranging from early childhood to the ninth decade of life. In addition to the classical triad, several associated signs and symptoms have been reported earlier such as lethargy, bradycardia, hypotension, altered sensorium, diffuse slowing on EEG, hematological abnormalities, and possible catatonic signs [Table 1].
There was thrombocytopenia in our patient whenever he had an episode, and one report of leucopenia in the beginning of his illness. Hematological abnormalities such as anemia, leucopenia, and thrombocytopenia have been reported in some earlier case reports also.,,,,,, A possible reason for the development of thrombocytopenia in our patient was severe hypothermia. It has been reported in literature that exposure to very low environmental temperatures can lead to a fall in core body temperature, which in turn can lead to bone marrow suppression and thrombocytopenia.
In our patient, the states of stupor and catatonia could not be explained entirely on the basis of this incidental finding on MRI brain. Hence, he was repeatedly misdiagnosed to be suffering from meningitis, depression, and autoimmune encephalitis by physicians, psychiatrists, and neurologists, before a final diagnosis of Shapiro syndrome could be made. The emphasis of the investigations and treatment was on the condition of stupor instead of hyperhidrosis, which led to the missing out of the actual diagnosis. Some previous case reports on Shapiro syndrome have also described associated altered sensorium ranging from delirium to coma.,,,,,,, Patients with moderate to severe accidental hypothermia may also present with altered consciousness. This could be the reason for the initial admissions of the patient in a state of stupor. However, it was not suspected in this patient because our hospital is in subtropical and plain climatic zone where patients with hypothermia are seldom brought. In our patient, the temperature recording was not carried out properly during the initial admissions and hypothermia was missed. Shapiro syndrome presenting with catatonia has not been described directly in literature. Yet in some case reports, features suggestive of catatonia have been reported, for example, mutism or little speech, immobility, unresponsiveness, blank facial expressions, and withdrawn behaviour.,,,,,,, A plethora of conditions have been reported to present with catatonia, some of which are encephalitis, epilepsy, head injury, endocrinological disorders, infections, drug induced lethargy, metabolic abnormalities, and psychiatric conditions., The pathogenesis of catatonia involves an alteration in the connectivity of the orbitofrontal cortex and parietal cortex. As no other known cause of catatonia was present in our patient, hypothermia might have been the possible reason behind it.
A diagnosis of autoimmune encephalitis was also considered because the patient had shown response to steroid pulse therapy during one of his hospital admissions. However, he did not improve with the second pulse dose of steroids. Autoimmune encephalitis is a relatively common but very difficult-to-diagnose phenomenon. It usually presents with seizures, psychiatric disturbances, memory impairment, and altered consciousness. There is a gamut of antibodies proposed to cause autoimmune encephalitis with varying overlapping psychiatric and neurological abnormalities. Though his symptoms matched with both anti-N-methyl-D-aspartate and anti-voltage gated potassium channel (VGKC) autoimmune encephalitis, serum sample was negative for both.
The etiopathogenesis of Shapiro's syndrome is still obscure. It has been hypothesized to be due to associated hypothalamic dysfunction,, or inadequate adrenergic activity in the brain., In some case reports, the symptoms improved with clonidine,,,,,, which is an alpha- 2 adrenergic agonist, and in a fewer case reports, it improved with cyproheptadine, a serotonin antagonist., In our patient, there was relapse of hyperhidrosis on clonidine and the addition of cyproheptadine led to improvement.
Hence, this was a rare case of Shapiro syndrome associated with thrombocytopenia and catatonia which led to diagnostic difficulties. Future research is needed to elucidate its etiopathogenesis and formulate a conclusive plan of management.
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[Figure 1], [Figure 2]